ORCID Profile
0000-0001-7840-0934
Current Organisations
AgResearch Ltd
,
The University of Newcastle
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Publisher: American Association for Cancer Research (AACR)
Date: 30-04-2017
DOI: 10.1158/0008-5472.CAN-16-1663
Abstract: Myc oncoproteins exert tumorigenic effects by regulating expression of target oncogenes. Histone H3 lysine 79 (H3K79) methylation at Myc-responsive elements of target gene promoters is a strict prerequisite for Myc-induced transcriptional activation, and DOT1L is the only known histone methyltransferase that catalyzes H3K79 methylation. Here, we show that N-Myc upregulates DOT1L mRNA and protein expression by binding to the DOT1L gene promoter. shRNA-mediated depletion of DOT1L reduced mRNA and protein expression of N-Myc target genes ODC1 and E2F2. DOT1L bound to the Myc Box II domain of N-Myc protein, and knockdown of DOT1L reduced histone H3K79 methylation and N-Myc protein binding at the ODC1 and E2F2 gene promoters and reduced neuroblastoma cell proliferation. Treatment with the small-molecule DOT1L inhibitor SGC0946 reduced H3K79 methylation and proliferation of MYCN gene– lified neuroblastoma cells. In mice xenografts of neuroblastoma cells stably expressing doxycycline-inducible DOT1L shRNA, ablating DOT1L expression with doxycycline significantly reduced ODC1 and E2F2 expression, reduced tumor progression, and improved overall survival. In addition, high levels of DOT1L gene expression in human neuroblastoma tissues correlated with high levels of MYCN, ODC1, and E2F2 gene expression and independently correlated with poor patient survival. Taken together, our results identify DOT1L as a novel cofactor in N-Myc–mediated transcriptional activation of target genes and neuroblastoma oncogenesis. Furthermore, they characterize DOT1L inhibitors as novel anticancer agents against MYCN- lified neuroblastoma. Cancer Res 77(9) 2522–33. ©2017 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479843.V1
Abstract: Supplementary Figure S4. Combination of the BET bromodomain inhibitor I-BET762 and chemotherapy agents, but not proteasome inhibitors, induces cytotoxicity to normal cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479837.V1
Abstract: Supplementary Figure S6. OTX015 and carfilzomib exert synergistic anticancer effects partly by inducing oxidative stress and endoplasmic reticulum stress.
Publisher: Elsevier BV
Date: 2010
DOI: 10.1038/MODPATHOL.2009.129
Abstract: The serum level of lactate dehydrogenase (LDH) is an important predictor of prognosis and treatment response in melanoma patients. It is unknown whether the expression of LDH-5 in tissue sections also has prognostic significance and whether it is related to the expression of the anti-apoptotic proteins, Bcl-2, Bcl-XL and Mcl-1, and endoplasmic reticulum stress protein glucose-regulated protein 78 (GRP78). Identification of an association between LDH-5 expression and anti-apoptotic proteins may have important therapeutic implications for melanoma patients. Sections from 159 pigmented lesions, including nevi and melanoma at different stages of progression were studied by immunohistochemistry. Correlation of LDH-5 expression with clinicopathological factors and with the expression of Bcl-2, Bcl-XL, Mcl-1 and GRP78 was examined. LDH-5 was detected at low levels in 6 of 10 compound nevi (60%) and 6 of 10 dysplastic nevi (60%). The percentage of positive cases was greater in thin ( 1.0 mm) (95%) and in metastatic melanoma in the skin (100%) and lymph node (81%). The immunoreactive score was highly related to progression of melanoma (P<0.0001). LDH-5 expression was positively associated with increasing tumor thickness (P=0.02) and dermal tumor mitotic rate (P=0.02). LDH-5 above the median immunoreactive score was associated with reduced disease-free survival and overall survival (P<0.02). LDH-5 expression was negatively associated with Bcl-2 expression. In contrast, LDH-5 expression was strongly associated with Bcl-XL and Mcl-1 expression and also positively associated with GRP78 expression (P<0.0001). The low Bcl-2 expression in melanomas with high LDH-5 expression provides an explanation for the poor response of patients with high serum LDH levels to treatment with the Bcl-2 antisense drug 'Genasense'. The strong correlation of LDH-5 expression with Mcl-1 expression suggests that treatment strategies inhibiting the activity of Mcl-1 in melanoma patients should be investigated.
Publisher: Informa UK Limited
Date: 26-05-2016
Publisher: Wiley
Date: 29-07-2021
DOI: 10.1002/JEQ2.20259
Abstract: Manure application to land and deposition of urine and dung by grazing animals are major sources of ammonia (NH 3 ) and nitrous oxide (N 2 O) emissions. Using data on NH 3 and N 2 O emissions following land‐applied manures and excreta deposited during grazing, emission factors (EFs) disaggregated by climate zone were developed, and the effects of mitigation strategies were evaluated. The NH 3 data represent emissions from cattle and swine manures in temperate wet climates, and the N 2 O data include cattle, sheep, and swine manure emissions in temperate wet/dry and tropical wet/dry climates. The NH 3 EFs for broadcast cattle solid manure and slurry were 0.03 and 0.24 kg NH 3 –N kg –1 total N (TN), respectively, whereas the NH 3 EF of broadcast swine slurry was 0.29. Emissions from both cattle and swine slurry were reduced between 46 and 62% with low‐emissions application methods. Land application of cattle and swine manure in wet climates had EFs of 0.005 and 0.011 kg N 2 O–N kg –1 TN, respectively, whereas in dry climates the EF for cattle manure was 0.0031. The N 2 O EFs for cattle urine and dung in wet climates were 0.0095 and 0.002 kg N 2 O–N kg –1 TN, respectively, which were three times greater than for dry climates. The N 2 O EFs for sheep urine and dung in wet climates were 0.0043 and 0.0005, respectively. The use of nitrification inhibitors reduced emissions in swine manure, cattle urine/dung, and sheep urine by 45–63%. These enhanced EFs can improve national inventories however, more data from poorly represented regions (e.g., Asia, Africa, South America) are needed.
Publisher: Impact Journals, LLC
Date: 13-10-2016
Publisher: Impact Journals, LLC
Date: 09-05-2017
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479828.V1
Abstract: Supplementary Table S1. Primary screening of the Food and Drug Administration-Approved Oncology Drugs (AODs) Set IV from the US National Cancer Institute for BET bromodomain inhibitor enhancers.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1038/MODPATHOL.3800750
Abstract: Members of the Bcl-2 family of antiapoptotic proteins (Bcl-2, Bcl-XL and Mcl-1) are key regulators of apoptosis. The purpose of the present study was to examine and better define the role of Bcl-2, Bcl-XL and Mcl-1 in the progression of melanoma. Immunohistochemical staining for Bcl-2, Bcl-XL and Mcl-1 was performed on paraffin sections of 100 cases of benign nevi, primary melanoma and metastatic melanoma. Expression was correlated with histopathologic features, clinical progress and expression of transcription factors (AP-2, MITF and p-Stat3). Bcl-2 was expressed in 100% of benign nevi and thin melanoma ( 1.0 mm) (88%), subcutaneous (62%) and lymph node metastases (35%). In contrast, Bcl-XL and Mcl-1 were expressed at lower levels in nevi and thin melanoma compared to Bcl-2 but their expression was much higher in thick melanoma and in subcutaneous and lymph node metastases (P<0.0001). Bcl-2 expression was negatively associated with tumor thickness (P<0.05) but Bcl-XL expression increased with increasing tumor thickness (P<0.05) and dermal tumor mitotic rate (P<0.05). Similarly Mcl-1 expression increased with increasing tumor thickness (P<0.09) and dermal tumor mitotic rate (P<0.17). Bcl-2 expression was positively correlated with expression of the transcription factors microphthalmia transcription factor (MITF) and nuclear AP-2 whereas Bcl-XL (and Mcl-1) expression were positively correlated with p-Stat3. This study is the first to show a clear dissociation between changes in Bcl-2 expression (downregulation) and Bcl-XL, Mcl-1 expression (upregulation) during progression of melanoma. The results were also consistent with a role for AP-2 and MITF in regulation of Bcl-2 and pStat3 in regulation of Bcl-XL. These findings have important implications for the development of treatments targeting antiapoptotic proteins in patients with melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479834.V1
Abstract: Supplementary Figure S7. OTX015 and carfilzomib synergistically improve mouse survival in a PDX model of TERT-rearranged neuroblastoma.
Publisher: American Geophysical Union (AGU)
Date: 08-2016
DOI: 10.1002/2016JC011691
Publisher: Research Square Platform LLC
Date: 11-12-2020
DOI: 10.21203/RS.3.RS-122179/V1
Abstract: Genomic lification of the distal portion of chromosome 3q, which encodes a number of oncogenic proteins, is one of the most frequent chromosomal abnormalities in malignancy. Here we functionally characterise a non-protein product of the 3q region, the long noncoding RNA (lncRNA) PLANE, which is upregulated in erse cancer types through copy number gain as well as E2F1-mediated transcriptional activation. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, thus leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. In consequence, PLANE promotes cancer cell proliferation and tumorigenicity and its upregulation is associated with poor patient outcomes. These results uncover the function and regulation of PLANE and suggest that PLANE may constitute a therapeutic target in the pan-cancer context.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2012
DOI: 10.1038/CDD.2012.147
Publisher: Elsevier BV
Date: 08-2011
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479846.V1
Abstract: Supplementary Figure S3. Screening for Approved Oncology Drugs (AODs) exerting synergistic anticancer effects with BET bromodomain inhibitors against TERT-rearranged neuroblastoma cells.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.MOLCEL.2021.11.017
Abstract: Non-covalent complexes of glycolytic enzymes, called metabolons, were postulated in the 1970s, but the concept has been controversial. Here we show that a c-Myc-responsive long noncoding RNA (lncRNA) that we call glycoLINC (gLINC) acts as a backbone for metabolon formation between all four glycolytic payoff phase enzymes (PGK1, PGAM1, ENO1, and PKM2) along with lactate dehydrogenase A (LDHA). The gLINC metabolon enhances glycolytic flux, increases ATP production, and enables cell survival under serine deprivation. Furthermore, gLINC overexpression in cancer cells promotes xenograft growth in mice fed a diet deprived of serine, suggesting that cancer cells employ gLINC during metabolic reprogramming. We propose that gLINC makes a functional contribution to cancer cell adaptation and provide the first ex le of a lncRNA-facilitated metabolon.
Publisher: Wiley
Date: 03-2009
DOI: 10.1111/J.1365-2559.2009.03242.X
Abstract: Glucose-regulated protein 78 (GRP78) is a protein translated in response to endoplasmic reticulum (ER) stress that has been implicated in the pathogenesis and resistance to therapy of a variety of cancers. The aim of this study was to investigate its expression and role in the development and progression of human melanoma. The immunohistochemical expression of GRP78 in naevi, primary melanoma and melanoma metastases from 171 patients was correlated with clinicopathological factors and patient survival. The GRP78 immunoreactivity score (IRS) was 0.2 in compound naevi, 0.65 in dysplastic naevi, 4.65 in naevi adjacent to primary melanoma, 2.4 in melanoma in situ, 11.2 in thin ( 1.0 mm) primary melanoma. It was 18 and 17.3 in subcutaneous and lymph node metastases, respectively (P 25 were significantly lower than in melanoma patients with IRS <25. GRP78 expression appears to correlate with known correlates of melanoma progression and survival and requires further evaluation as a prognostic biomarker in melanoma.
Publisher: MDPI AG
Date: 05-03-2021
Abstract: Quiescent cancer cells (QCCs) are cancer cells that are reversibly suspended in G0 phase with the ability to re-enter the cell cycle and initiate tumor growth, and, ultimately, cancer recurrence and metastasis. QCCs are also therapeutically challenging due to their resistance to most conventional cancer treatments that selectively act on proliferating cells. Considering the significant impact of QCCs on cancer progression and treatment, better understanding of appropriate experimental models, and the evaluation of QCCs are key questions in the field that have direct influence on potential pharmacological interventions. Here, this review focuses on existing and emerging preclinical models and detection methods for QCCs and discusses their respective features and scope for application. By providing a framework for selecting appropriate experimental models and investigative methods, the identification of the key players that regulate the survival and activation of QCCs and the development of more effective QCC-targeting therapeutic agents may mitigate the consequences of QCCs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479831.V1
Abstract: Re - Revised Supplementary Materials & Methods
Publisher: Springer Science and Business Media LLC
Date: 07-06-2018
DOI: 10.1038/S41419-018-0714-7
Abstract: Many recent studies have uncovered the necessary role for the receptor-interacting protein kinase 1 (RIP1) in regulating apoptosis and necrosis that cells undergo in response to various cellular stresses. However, the functional significance of RIP1 in promoting cancer cell survival remains poorly understood. Here, we report that RIP1 was upregulated and contributed to both intrinsic and acquired resistance of melanoma cells to BRAF/MEK inhibitors through activation of NF-κB. Strikingly, Snail1-mediated suppression of CYLD played a crucial role in promoting RIP1 expression upon ERK activation, particularly, in melanoma cells with acquired resistance to BRAF inhibitors. In addition, RIP1 kinase activity was not required for melanoma cells to survive BRAF/MEK inhibition as RIP1 mediated NF-κB activation through its intermediate domain. Collectively, our findings reveal that targeting RIP1 in combination with BRAF/MEK inhibitors is a potential approach in the treatment of the disease.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479852.V1
Abstract: Supplementary Figure S1. TERT induces TERT-rearranged neuroblastoma cell proliferation and cell cycle progression through a telomerase-independent mechanism.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2013
DOI: 10.1038/ONC.2013.45
Abstract: Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAF(V600E) signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma.
Publisher: Impact Journals, LLC
Date: 09-11-2015
Publisher: Springer Science and Business Media LLC
Date: 17-06-2014
DOI: 10.1038/ONC.2013.237
Abstract: Increased global protein synthesis and selective translation of mRNAs encoding proteins contributing to malignancy is common in cancer cells. This is often associated with elevated expression of eukaryotic translation initiation factor 4 (eIF4E), the rate-limiting factor of cap-dependent translation initiation. We report here that in human melanoma downregulation of miR-768-3p as a result of activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway has an important role in the upregulation of eIF4E and enhancement in protein synthesis. Melanoma cells displayed increased nascent protein production and elevated eIF4E expression, which was associated with the downregulation of miR-768-3p that was predicted to target the 3'-untranslated region of the eIF4E mRNA. Overexpression of miR-768-3p led to the downregulation of the endogenous eIF4E protein, reduction in nascent protein synthesis and inhibition of cell survival and proliferation. These effects were efficiently reversed when eIF4E was co-overexpressed in melanoma cells. On the other hand, introduction of anti-miR-768-3p into melanocytes upregulated endogenous eIF4E protein expression and increased global protein synthesis. Downregulation of miR-768-3p appeared to be mediated by activation of the MEK/ERK pathway, in that treatment of BRAF(V600E) melanoma cells with the mutant BRAF inhibitor PLX4720 or exposure of either BRAF(V600E) or wild-type BRAF melanoma cells to the MEK inhibitor U0126 resulted in the upregulation of miR-768-3p and inhibition of nascent protein synthesis. This inhibition was partially blocked in cells cointroduced with anti-miR-768-3p. Significantly, miR-768-3p was similarly downregulated, which was inversely associated with the expression levels of eIF4E in fresh melanoma isolates. Taken together, these results identify downregulation of miR-768-3p and subsequent upregulation of eIF4E as an important mechanism in addition to phosphorylation of eIF4E responsible for MEK/ERK-mediated enhancement of protein synthesis in melanoma.
Publisher: Springer Science and Business Media LLC
Date: 07-11-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 26-11-2018
Abstract: Here, we report that the long noncoding RNA (lncRNA) ovarian adenocarcinoma- lified lncRNA (OVAAL) is a mediator of cancer cell resistance, counteracting the effects of apoptosis-inducing agents acting through both the extrinsic and intrinsic pathways. Building upon previous reports associating OVAAL lification with ovarian and endometrial cancers, we now show that OVAAL overexpression occurs during the pathogenesis of colorectal cancer and melanoma. Mechanistically, our findings also establish that OVAAL expression more generally contributes a prosurvival role to cancer cells under steady-state conditions. OVAAL accomplishes these actions utilizing distinct functional modalities: one promoting activation of RAF/MEK/ERK signaling and the other blocking cell entry into senescence. Our study demonstrates that expression of a single OVAAL in cancer cells drives two distinct but coordinated actions contributing to cancer pathology.
Publisher: Springer Science and Business Media LLC
Date: 26-02-2013
DOI: 10.1038/NCOMMS2489
Publisher: Wiley
Date: 03-03-2022
Abstract: Active crosstalk between the nervous system and breast cancer cells has been experimentally demonstrated in vitro and in animal models. However, low frequencies of peripheral nerve presence in human breast cancers reported in previous studies (~30% of cases) potentially negate a major role of the nervous system in breast cancer development and progression. This study aimed to clarify the incidence of nerves within human breast cancers and to delineate associations with clinicopathological features. Immunohistochemical staining was conducted in formalin‐fixed paraffin‐embedded breast cancer tissue sections using antibodies against the pan‐neuronal markers protein gene product 9.5 and growth‐associated protein 43, and the sympathetic nerve‐specific marker tyrosine hydroxylase. Nerve trunks and isolated nerve fibers were quantitated. The chi‐squared test was used to determine the associations between nerve counts and clinicopathological parameters. The log‐rank test was used to compare differences in patient progression‐free survival (PFS) and overall survival (OS). The overall frequency of peripheral nerves in breast cancers was 85%, a markedly higher proportion than reported previously. Of note, most nerves present in breast cancers were of the sympathetic origin. While high density of nerve trunks or isolated nerve fibers was associated with poor PFS and OS of patients, high nerve trunk density appeared also to predict poor patient PFS independently of lymph node metastasis. Innervation of breast cancers is a common event correlated with poor patient outcomes. These findings support the notion that the nervous system plays an active role in breast cancer pathogenesis.
Publisher: Elsevier BV
Date: 08-2022
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479837
Abstract: Supplementary Figure S6. OTX015 and carfilzomib exert synergistic anticancer effects partly by inducing oxidative stress and endoplasmic reticulum stress.
Publisher: Springer Science and Business Media LLC
Date: 05-11-2019
DOI: 10.1038/S41467-019-12971-3
Abstract: The majority of patients with neuroblastoma due to MYCN oncogene lification and consequent N-Myc oncoprotein over-expression die of the disease. Here our analyses of RNA sequencing data identify the long noncoding RNA lncNB1 as one of the transcripts most over-expressed in MYCN - lified, compared with MYCN -non- lified, human neuroblastoma cells and also the most over-expressed in neuroblastoma compared with all other cancers. lncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. The GTPase-activating protein DEPDC1B induces ERK protein phosphorylation and N-Myc protein stabilization. Importantly, lncNB1 knockdown abolishes neuroblastoma cell clonogenic capacity in vitro and leads to neuroblastoma tumor regression in mice, while high levels of lncNB1 and RPL35 in human neuroblastoma tissues predict poor patient prognosis. This study therefore identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targets.
Publisher: Oxford University Press (OUP)
Date: 06-2014
DOI: 10.1093/JNCI/DJU113
Abstract: Patients with neuroblastoma due to the lification of a 130-kb genomic DNA region containing the MYCN oncogene have poor prognoses. Bioinformatics data were used to discover a novel long noncoding RNA, lncUSMycN, at the 130-kb licon. RNA-protein pull-down assays were used to identify proteins bound to lncUSMycN RNA. Kaplan-Meier survival analysis, multivariable Cox regression, and two-sided log-rank test were used to examine the prognostic value of lncUSMycN and NonO expression in three cohorts of neuroblastoma patients (n = 47, 88, and 476, respectively). Neuroblastoma-bearing mice were treated with antisense oligonucleotides targeting lncUSMycN (n = 12) or mismatch sequence (n = 13), and results were analyzed by multiple comparison two-way analysis of variance. All statistical tests were two-sided. Bioinformatics data predicted lncUSMycN gene and RNA, and reverse-transcription polymerase chain reaction confirmed its three exons and two introns. The lncUSMycN gene was co lified with MYCN in 88 of 341 human neuroblastoma tissues. lncUSMycN RNA bound to the RNA-binding protein NonO, leading to N-Myc RNA upregulation and neuroblastoma cell proliferation. High levels of lncUSMycN and NonO expression in human neuroblastoma tissues independently predicted poor patient prognoses (lncUSMycN: hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.06 to 3.28, P = .03 NonO: HR = 2.48, 95% CI = 1.34 to 4.57, P = .004). Treatment with antisense oligonucleotides targeting lncUSMycN in neuroblastoma-bearing mice statistically significantly hindered tumor progression (P < .001). Our data demonstrate the important roles of lncUSMycN and NonO in regulating N-Myc expression and neuroblastoma oncogenesis and provide the first evidence that lification of long noncoding RNA genes can contribute to tumorigenesis.
Publisher: Oxford University Press (OUP)
Date: 29-10-2014
DOI: 10.1093/JNCI/DJU359
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.HUMPATH.2006.04.026
Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in melanoma by interaction with death receptors TRAIL-R1 (DR4) or TRAIL-R2 (DR5) on melanoma cells or resists apoptosis by interaction with decoy receptors TRAIL-R3 (DcR1) or TRAIL-R4 (DcR2). Studies on cell lines suggest that there is a wide variation in TRAIL death receptor expression however, their expression on excised human melanoma is not well documented. In view of this, we studied death receptor expression on melanomas using monoclonal antibodies specific for these receptors. Immunohistochemical staining for DR4, DR5, and DcR1/DcR2 was performed on formalin-fixed paraffin-embedded sections of 100 cases of primary melanoma, metastatic melanoma, and benign nevi. Percentage expressions of DR4 versus DR5 in benign nevi, primary melanoma, and melanoma metastases were 40% versus 90%, 69% versus 98%, and 55% versus 66%, respectively. There were significant differences in the mean percentage of DR5-positive cells between different groups of melanocytic lesions. Percent expression was higher in thin (< or =1.0 mm) compared with thick primary melanoma (88.9% versus 66.9%), and expression was less in subcutaneous metastases (49%) and lymph node metastases (30.6%) (P < .005). Expression was also higher in compound nevi (57%) than dysplastic nevi (49%). DcR1/DcR2 was found in 75% of benign nevi, 62% of primary melanomas, and 74% melanoma metastases. The results showed a wide variation in the expression of death receptors for TRAIL between and within primary and metastatic melanoma and a decreased expression on the thick primary melanoma and metastatic melanoma. This suggests that melanoma may not respond to treatment with TRAIL unless given with agents that increase the expression of TRAIL death receptors.
Publisher: American Association for Cancer Research (AACR)
Date: 14-11-2017
DOI: 10.1158/0008-5472.CAN-17-1965
Abstract: MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA however, there is little understanding of how MTH1 itself is regulated. Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment. Cancer Res 77(22) 6226–39. ©2017 AACR.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.BBAMCR.2010.07.002
Abstract: CD36/FAT is a transmembrane glycoprotein that functions in the cellular uptake of long-chain fatty acids and also as a scavenger receptor. As such it plays an important role in lipid homeostasis and, pathophysiologically, in the progression of type 2 diabetes and atherosclerosis. CD36 expression is tightly regulated at the levels of both transcription and translation. Here we show that its expression and location are also regulated post-translationally, by palmitoylation. Although palmitoylation of CD36 was not required for receptor maturation and cell surface expression, inhibition of palmitoylation either pharmacologically with cerulenin or by mutation of the relevant cysteines delayed processing at the ER and trafficking through the secretory pathway. The absence of palmitoylation also reduced the half life of the CD36 protein. Additionally, the CD36 palmitoylation mutant did not incorporate efficiently into lipid rafts, a site known to be required for its function of fatty acid uptake, and this reduced the efficiency of uptake of oxidized low density lipoprotein. These findings provide an added level of sophistication where translocation of CD36 to the plasma membrane may be physiologically regulated by palmitoylation.
Publisher: Wiley
Date: 18-12-2008
DOI: 10.1016/J.FEBSLET.2007.12.014
Abstract: We have previously shown that Docetaxel-induced variable degrees of apoptosis in melanoma. In this report, we studied the beta-tubulin repertoire of melanoma cell lines and show that class III beta-tubulin expression correlated with Docetaxel-resistance. Sensitive cells showed low levels of class III beta-tubulin with little microtubular incorporation, whereas class III beta-tubulin expression was higher in resistant cells and was incorporated into the cytoskeleton. As proof of concept, abrogation of class III by siRNA reverted Docetaxel-resistant cells to a sensitive phenotype, restoring the microtubular polymerisation response and promoting high levels of apoptosis through Bax activation. These results suggest that phenotypic expression of beta-tubulin class III in melanoma may help identify patients with melanoma that can respond to taxanes.
Publisher: Public Library of Science (PLoS)
Date: 05-08-2013
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2015
DOI: 10.1158/0008-5472.CAN-14-2199
Abstract: Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here, we report that RIP1 functions as an oncogenic driver in human melanoma. Although RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a small proportion of melanoma cells, RIP1 overexpression enhanced proliferation in the remaining cells. Mechanistic investigations revealed that the proliferative effects of RIP1 overexpression were mediated by NF-κB activation. Strikingly, ectopic expression of RIP1 enhanced the proliferation of primary melanocytes, triggering their anchorage-independent cell growth in an NF-κB–dependent manner. We identified DNA copy-number gain and constitutive ubiquitination by a TNFα autocrine loop mechanism as two mechanisms of RIP1 upregulation in human melanomas. Collectively, our findings define RIP1 as an oncogenic driver in melanoma, with potential implications for targeting its NF-κB–dependent activation mechanism as a novel approach to treat this disease. Cancer Res 75(8) 1736–48. ©2015 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479840
Abstract: Supplementary Figure S5. BET bromodomain inhibitors and proteasome inhibitors exert synergistic anticancer effects against TERT-rearranged neuroblastoma cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479846
Abstract: Supplementary Figure S3. Screening for Approved Oncology Drugs (AODs) exerting synergistic anticancer effects with BET bromodomain inhibitors against TERT-rearranged neuroblastoma cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479843
Abstract: Supplementary Figure S4. Combination of the BET bromodomain inhibitor I-BET762 and chemotherapy agents, but not proteasome inhibitors, induces cytotoxicity to normal cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479828
Abstract: Supplementary Table S1. Primary screening of the Food and Drug Administration-Approved Oncology Drugs (AODs) Set IV from the US National Cancer Institute for BET bromodomain inhibitor enhancers.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530307.V1
Abstract: AbstractPurpose: i TERT /i gene rearrangement with transcriptional superenhancers leads to i TERT /i overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with i TERT /i -rearranged neuroblastoma. Experimental Design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with i TERT /i -rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. Results: The BET bromodomain protein BRD4 promoted i TERT /i -rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced i TERT /i -rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with i TERT /i -rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with i TERT /i -rearranged neuroblastoma. /
Publisher: Oxford University Press (OUP)
Date: 12-07-2012
Abstract: Emerging evidence has pointed to biological roles of melanoma-associated antigens (MAGEs) in cancer development, progression and resistance to treatment. However, the mechanisms involved remain to be fully elucidated. In this report, we show that one of the MAGE proteins, MAGE-D2, suppresses the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 2 (TRAIL-R2) and plays an important role in protecting melanoma cells from apoptosis induced by TRAIL. MAGE-D2 was commonly expressed at increased levels in melanoma cells compared with melanocytes. Although its inhibition by small interfering RNA (siRNA) did not cause cell death, it rendered melanoma cells more sensitive to TRAIL-induced apoptosis. This was associated with enhanced formation of TRAIL death-inducing signaling complex and up-regulation of TRAIL-R2, and was blocked by a recombinant TRAIL-R2/Fc chimeric protein or siRNA knockdown of TRAIL-R2. Regulation of TRAIL-R2 by MAGE-D2 appeared to be mediated by p53, in that knockdown MAGE-D2 did not up-regulate TRAIL-R2 in p53-null or mutant p53 melanoma cells. In addition, inhibition of MAGE-D2 did not result in up-regulation of TRAIL-R2 in wild-type p53 cell lines with p53 inhibited by short hairpin RNA. Indeed, knockdown of MAGE-D2 led to up-regulation of p53 due to a transcriptional increase. The regulatory effect of MAGE-D2 on TRAIL-R2 expression and TRAIL-induced apoptosis was recapitulated in studies on fresh melanoma isolates. Taken together, these results identify the expression of MAGE-D2 as an important mechanism that inhibit TRAIL-induced apoptosis and suggest that targeting MAGE-D2 may be a useful strategy in improving the therapeutic efficacy of TRAIL in melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 22-07-2148
DOI: 10.1158/0008-5472.CAN-18-1886
Abstract: Two novel p53-responsive microRNAs whose distinct mechanisms of action both stabilize p27 to promote cell quiescence and may serve as therapeutic avenues for improving outcomes of cancer treatment.
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1593/TLO.13277
Publisher: Proceedings of the National Academy of Sciences
Date: 29-01-2018
Abstract: We report in this article that c-Myc-mediated repression of lncRNA IDH1-AS1 sustains activation of the Warburg effect by HIF1α under normoxic conditions. IDH1-AS1 would otherwise enhance IDH1 enzymatic activity through promoting its homodimerization, leading to increased production of α-KG, which, along with decreases in ROS levels similarly resulting from increased IDH1 activity, causes down-regulation of HIF1a and a reduction in glycolysis. Collectively, our results have identified a signaling axis c-Myc-(IDH1-AS1)-IDH1-αKG/ROS-HIF1α that is important for activation of the Warburg effect under normoxia. Moreover, the results reveal IDH1 as a member of c-Myc-responsive metabolic enzymes and demonstrate that c-Myc plays an important part in balancing mitochondrial respiration and glycolysis to ensure glycolysis be executed efficiently in cancer cells under normoxia.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2019
DOI: 10.1007/S00267-019-01242-Y
Abstract: Although the link between agriculture and diffuse water pollution has been understood for decades, there is still a need to implement effective measures to address this issue. In countries with light-touch regulation, such as New Zealand and Australia, most efforts to promote environmental management practices have relied on voluntary initiatives such as participatory research and extension programmes the success of which is largely dependent on farmers’ willingness and ability to adopt these practices. Increased understanding of the factors influencing farmer decision-making in this area would aid the promotion of effective advisory services. This study provides insights from 52 qualitative interviews with farmers and from observations of nine farmer meetings and field days. We qualitatively identify factors that influence farmer decision-making regarding the voluntary uptake of water quality practices and develop a typology for categorising farmers according to the factors that influence their decision-making. We find that in light-touch regulated countries certainty around policy and also around the effectiveness of practices is essential, particularly for farmers who delay action until compelled to act due to succession or regulation. The contribution of this paper is threefold: (i) it identifies factors influencing decision-making around the uptake of water quality practices in a light-touch regulated country (ii) it develops a typology of different farmer types and (iii) it provides recommendations on policy approaches for countries with light-touch regulation, which has potential relevance for any countries facing changes regarding their agricultural policy, such as post-Brexit policy in the UK.
Publisher: Elsevier
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 29-09-2018
DOI: 10.1038/ONC.2011.87
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479831
Abstract: Re - Revised Supplementary Materials & Methods
Publisher: Informa UK Limited
Date: 02-01-2016
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479840.V1
Abstract: Supplementary Figure S5. BET bromodomain inhibitors and proteasome inhibitors exert synergistic anticancer effects against TERT-rearranged neuroblastoma cells.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479834
Abstract: Supplementary Figure S7. OTX015 and carfilzomib synergistically improve mouse survival in a PDX model of TERT-rearranged neuroblastoma.
Publisher: Springer Science and Business Media LLC
Date: 18-06-2021
DOI: 10.1038/S41467-021-24099-4
Abstract: Genomic lification of the distal portion of chromosome 3q, which encodes a number of oncogenic proteins, is one of the most frequent chromosomal abnormalities in malignancy. Here we functionally characterise a non-protein product of the 3q region, the long noncoding RNA (lncRNA) PLANE, which is upregulated in erse cancer types through copy number gain as well as E2F1-mediated transcriptional activation. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, thus leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. This is, at least in part, responsible for PLANE-mediated promotion of cancer cell proliferation and tumorigenicity. These results uncover the function and regulation of PLANE and suggest that PLANE may constitute a therapeutic target in the pan-cancer context.
Publisher: Springer Science and Business Media LLC
Date: 13-12-2019
DOI: 10.1007/S00418-019-01835-Y
Abstract: CD44 is a transmembrane receptor that acts as adhesion protein, fundamentally recognizing hyaluronan, an essential component of the extracellular matrix. It has a well-established functional association with cancer metastasis, particularly the CD44 variant forms which are considered essential markers of cancer stem cells. CD44 itself lacks intrinsic kinase activity but rather engages in signalling through specific interactions with kinases and other signalling components. Proteolysis within its transmembrane region also leads to release of the CD44 cytoplasmic domain, which can translocate to the nucleus and regulate transcription. A third signalling modality has been reported where the intact CD44 receptor translocates to the nucleus. Here, we investigated the latter using imaging techniques together with biochemical analyses. Our findings support observations where CD44 is cleaved prior to nuclear translocation and challenges the evidence for the presence of intact CD44 receptors in the cell nucleus. Conclusions regarding the presence of intact CD44 in the cell nucleus as a signalling modality, therefore, require re-evaluation. We highlight artefacts and common technical issues associated with these experiments that can lead to misinterpretation.
Publisher: American Association for Cancer Research (AACR)
Date: 05-03-2021
DOI: 10.1158/0008-5472.CAN-20-4107
Abstract: RNA N6-methyladenosine (m6A) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA m6A is regulated by the RNA m6A methyltransferases methyltransferase-like 3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1–2, YTHDF1–3, IGF2BP1–3, and SND1 (readers). These RNA m6A modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA m6A modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both in vitro and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA m6A modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA m6A modification protein expression or RNA m6A modification protein–induced resistance to cancer therapy.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2022
DOI: 10.1186/S13046-022-02452-9
Abstract: Distant metastasis is the major cause of clear cell renal cell carcinoma (ccRCC)-associated mortality. However, molecular mechanisms involved in ccRCC metastasis remain to be fully understood. With the increasing appreciation of the role of long non-coding RNAs (lncRNAs) in cancer development, progression, and treatment resistance, the list of aberrantly expressed lncRNAs contributing to ccRCC pathogenesis is expanding rapidly. Bioinformatics analysis was carried out to interrogate publicly available ccRCC datasets. In situ hybridization and qRT-PCR assays were used to test lncRNA expression in human ccRCC tissues and cell lines, respectively. Chromatin immunoprecipitation and luciferase reporter assays were used to examine transcriptional regulation of gene expression. Wound healing as well as transwell migration and invasion assays were employed to monitor ccRCC cell migration and invasion in vitro. ccRCC metastasis was also examined using mouse models in vivo. RNA pulldown and RNA immunoprecipitation were performed to test RNA–protein associations, whereas RNA-RNA interactions were tested using domain-specific chromatin isolation by RNA purification. MILIP expression was upregulated in metastatic compared with primary ccRCC tissues. The increased MILIP expression in metastatic ccRCC cells was driven by the transcription factor AP-2 gamma (TFAP2C). Knockdown of MILIP diminished the potential of ccRCC cell migration and invasion in vitro and reduced the formation of ccRCC metastatic lesions in vivo. The effect of MILIP on ccRCC cells was associated with alterations in the expression of epithelial-to-mesenchymal transition (EMT) hallmark genes. Mechanistically, MILIP formed an RNA-RNA duplex with the snail family transcriptional repressor 1 (Snai1) mRNA and bound to Y-box binding protein 1 (YBX1). This promoted the association between the YBX1 protein and the Snai1 mRNA, leading to increased translation of the latter. Snai1 in turn played an important role in MILIP-driven ccRCC metastasis. The TFAP2C-responsive lncRNA MILIP drives ccRCC metastasis. Targeting MILIP may thus represent a potential avenue for ccRCC treatment.
Publisher: Impact Journals, LLC
Date: 19-07-2016
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
Abstract: Despite advances in early diagnosis and the development of molecularly targeted therapy, curative treatment of colon cancer once it has metastasized is yet to be accomplished. This is closely associated with deregulated CRC cell proliferation and resistance to apoptosis. Here we reveal that upregulation of microRNA-645 (miR-645) through DNA copy number gain is responsible for enhanced proliferation and resistance to apoptosis in colon cancer. MiR-645 was upregulated in most colon cancer tissues related to adjacent normal mucosa. This appeared to be associated with lification of a section of chromosome 20q13.13, where miR-645 is located. Inhibition of miR-645 reduced proliferation and enhanced sensitivity to apoptosis triggered by the chemotherapeutic drugs 5-fluorouracil and cisplatin in CRC cells, and retarded colon cancer xenograft growth. Conversely, overexpression of miR-645 in normal colon epithelial cells enhanced proliferation and triggered anchorage-independent cell growth. Although SRY-related HMG-box 30 (SOX30) was identified as a miR-645 target, its expression was only partially affected by miR-645, suggesting that miR-645 is a fine-tuning mechanism of SOX30 expression. Moreover, overexpression of SOX30 only moderately inhibited promotion of CRC cell proliferation by miR-645, indicating that miR-645 may have more targets that contribute to its pro-proliferation effect in colon cancer. Together, this study reveals that miR-645 can regulate oncogenesis in colon cancer with SOX30 being one of its targets.
Publisher: Proceedings of the National Academy of Sciences
Date: 29-11-2022
Abstract: The protooncoprotein N-Myc, which is overexpressed in approximately 25% of neuroblastomas as the consequence of MYCN gene lification, has long been postulated to regulate DNA double-strand break (DSB) repair in neuroblastoma cells, but experimental evidence of this function is presently scant. Here, we show that N-Myc transcriptionally activates the long noncoding RNA MILIP to promote nonhomologous end-joining (NHEJ) DNA repair through facilitating Ku70–Ku80 heterodimerization in neuroblastoma cells. High MILIP expression was associated with poor outcome and appeared as an independent prognostic factor in neuroblastoma patients. Knockdown of MILIP reduced neuroblastoma cell viability through the induction of apoptosis and inhibition of proliferation, retarded neuroblastoma xenograft growth, and sensitized neuroblastoma cells to DNA-damaging therapeutics. The effect of MILIP knockdown was associated with the accumulation of DNA DSBs in neuroblastoma cells largely due to decreased activity of the NHEJ DNA repair pathway. Mechanistical investigations revealed that binding of MILIP to Ku70 and Ku80 increased their heterodimerization, and this was required for MILIP-mediated promotion of NHEJ DNA repair. Disrupting the interaction between MILIP and Ku70 or Ku80 increased DNA DSBs and reduced cell viability with therapeutic potential revealed where targeting MILIP using Gapmers cooperated with the DNA-damaging drug cisplatin to inhibit neuroblastoma growth in vivo. Collectively, our findings identify MILIP as an N-Myc downstream effector critical for activation of the NHEJ DNA repair pathway in neuroblastoma cells, with practical implications of MILIP targeting, alone and in combination with DNA-damaging therapeutics, for neuroblastoma treatment.
Publisher: Wiley
Date: 22-01-2021
DOI: 10.1002/JEQ2.20186
Abstract: Nitrous oxide (N 2 O), ammonia (NH 3 ), and methane (CH 4 ) emissions from the manure management chain of livestock production systems are important contributors to greenhouse gases (GHGs) and NH 3 emitted by human activities. Several studies have evaluated manure‐related emissions and associated key variables at regional, national, or continental scales. However, there have been few studies focusing on the drivers of these emissions using a global dataset. An international project was created (DATAMAN) to develop a global database on GHG and NH 3 emissions from the manure management chain (housing, storage, and field) to identify key variables influencing emissions and ultimately to refine emission factors (EFs) for future national GHG inventories and NH 3 emission reporting. This paper describes the “field” database that focuses on N 2 O and NH 3 EFs from land‐applied manure and excreta deposited by grazing livestock. We collated relevant information (EFs, manure characteristics, soil properties, and climatic conditions) from published peer‐reviewed research, conference papers, and existing databases. The database, containing 5,632 observations compiled from 184 studies, was relatively evenly split between N 2 O and NH 3 (56 and 44% of the EF values, respectively). The N 2 O data were derived from studies conducted in 21 countries on five continents, with New Zealand, the United Kingdom, Kenya, and Brazil representing 86% of the data. The NH 3 data originated from studies conducted in 17 countries on four continents, with the United Kingdom, Denmark, Canada, and The Netherlands representing 79% of the data. Wet temperate climates represented 90% of the total database. The DATAMAN field database is available at www.dataman.co.nz .
Publisher: Wiley
Date: 13-01-2023
Abstract: P53 inactivation occurs in about 50% of human cancers, where p53‐driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, this work shows that the E2F1‐responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53‐defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild‐type and p53‐mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53‐mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53‐mutant but not wild‐type p53 COAD patients. These results uncover an lncRNA mechanism that promotes p53‐defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 12-08-2008
DOI: 10.1158/0008-5472.CAN-08-0349
Abstract: We have previously shown that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress–induced apoptosis, and this involves activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway and expression of the apoptosis repressor with caspase recruitment domain (ARC) protein in the cells. In the present study, we show that up-regulation of the antiapoptotic Bcl-2 family member Mcl-1 is another mechanism critical for protection of melanoma cells against ER stress–induced apoptosis. Inhibition of Mcl-1 by small interference RNA (siRNA) rendered melanoma cells sensitive to apoptosis induced by the ER stress inducers thapsigargin and tunicamycin, but this sensitization was partially reversed by siRNA knockdown of PUMA or Noxa, as shown in Mcl-1–deficient melanoma cells. Both PUMA and Noxa were increased by ER stress through transcriptional up-regulation, but only up-regulation of Noxa was dependent on p53, whereas up-regulation of PUMA seemed to be mediated by a p53-independent mechanism(s). Up-regulation of Mcl-1 was also due to increased transcription that involved the IRE1α and activating transcription factor 6 signaling pathways of the unfolded protein response. In addition, activation of the MEK/ERK signaling pathway seemed to be necessary for optimal up-regulation of Mcl-1. Taken together, these results reveal the mechanisms of resistance of melanoma cells to apoptosis induction mediated by BH3-only proteins upon ER stress, and identify Mcl-1 as a target for the treatment of melanoma in combination with therapeutics that induce ER stress. [Cancer Res 2008 (16):6708–17]
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479849
Abstract: Supplementary Figure S2. BRD4 is required for TERT expression and cell proliferation in TERT-rearranged neuroblastoma cells.
Publisher: Elsevier BV
Date: 03-2016
Abstract: Evasion of immune system is a hallmark of cancer, which enables cancer cells to escape the attack from immune cells. Cancer cells can express many immune inhibitory signalling proteins to cause immune cell dysfunction and apoptosis. One of these inhibitory molecules is programmed death-ligand-1 (PD-L1), which binds to programmed death-1 (PD-1) expressed on T-cells, B-cells, dendritic cells and natural killer T-cells to suppress anti-cancer immunity. Therefore, anti-PD-L1 and anti-PD-1 antibodies have been used for the treatment of cancer, showing promising outcomes. However, only a proportion of patients respond to the treatments. Further understanding of the regulation of PD-L1 expression could be helpful for the improvement of anti-PD-L1 and anti-PD-1 treatments. Studies have shown that PD-L1 expression is regulated by signalling pathways, transcriptional factors and epigenetic factors. In this review, we summarise the recent progress of the regulation of PD-L1 expression in cancer cells and propose a regulatory model for unified explanation. Both PI3K and MAPK pathways are involved in PD-L1 regulation but the downstream molecules that control PD-L1 and cell proliferation may differ. Transcriptional factors hypoxia-inducible factor-1α and signal transducer and activation of transcription-3 act on the promoter of PD-L1 to regulate its expression. In addition, microRNAs including miR-570, miR-513, miR-197, miR-34a and miR-200 negatively regulate PD-L1. Clinically, it could increase treatment efficacy of targeted therapy by choosing those molecules that control both PD-L1 expression and cell proliferation.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1038/JID.2013.325
Abstract: Cancer cells commonly undergo chronic endoplasmic reticulum (ER) stress, to which the cells have to adapt for survival and proliferation. We report here that in melanoma cells intrinsic activation of the ER stress response/unfolded protein response (UPR) is, at least in part, caused by increased outputs of protein synthesis driven by oncogenic activation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) and promotes proliferation and protects against apoptosis induced by acute ER stress. Inhibition of oncogenic BRAF(V600E) or MEK-attenuated activation of inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) signaling of the UPR in melanoma cells. This was associated with decreased phosphorylation of eukaryotic initiation factor 4E (eIF4E) and nascent protein synthesis and was recapitulated by knockdown of eIF4E. In line with this, introduction of BRAF(V600E) into melanocytes led to increases in eIF4E phosphorylation and protein production and triggered activation of the UPR. Similar to knockdown of glucose-regulated protein 78 (GRP78), inhibition of XBP1 decelerated melanoma cell proliferation and enhanced apoptosis induced by the pharmacological ER stress inducers tunicamycin and thapasigargin. Collectively, these results reveal that potentiation of adaptation to chronic ER stress is another mechanism by which oncogenic activation of the MEK/ERK pathway promotes the pathogenesis of melanoma.
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.JID.2017.11.009
Abstract: Although the expression of programmed death-ligand 1 (PD-L1) is an important mechanism by which cancer cells evade the immune system, PD-L1 expression in cancer cells is commonly associated with patients' responses to treatment with anti-programmed death 1/PD-L1 antibodies. However, how PD-L1 expression is regulated in melanoma cells remains to be fully elucidated. Here we report that the class I histone deacetylase (HDAC) HDAC8 controls transcriptional activation of PD-L1 by a transcription complex consisting of transcription factors homeobox A5 and signal transducer and activator of transcription 3. Inhibition of HDAC8 upregulated PD-L1 in melanoma cells. This was due to an increase in the activity of a fragment of the PD-L1 gene promoter that is enriched with binding sites for both homeobox A5 and signal transducer and activator of transcription 3. Indeed, knockdown of homeobox A5 or signal transducer and activator of transcription 3 abolished upregulation of PD-L1 by HDAC8 inhibition. Moreover, homeobox A5 and signal transducer and activator of transcription 3 were physically associated and appeared interdependent in activating PD-L1 transcription. Functional studies showed that HDAC8-mediated regulation of PD-L1 expression participated in modulating anti-melanoma T-cell responses. Collectively, these results identify HDAC8 as an important epigenetic regulator of PD-L1 expression, with implications for better understanding of the interaction between melanoma cells and the immune system.
Publisher: Impact Journals, LLC
Date: 06-07-2016
Publisher: MDPI AG
Date: 17-12-2019
DOI: 10.3390/ANI9121158
Abstract: Between 2011 and 2016, small-scale farm trials were run across three dairy regions of New Zealand (Waikato, Canterbury, Otago) to compare the performance of typical regional farm systems with farm systems implementing a combination of mitigation options most suitable to the region. The trials ran for at least three consecutive years with detailed recording of milk production and input costs. Nitrate leaching per hectare of the milking platform (where lactating cows are kept) was estimated using either measurements (suction cups), models, or soil mineral nitrogen measurements. Post-trial, detailed farm information was used in the New Zealand greenhouse gas inventory methodology to calculate the emissions from all sources dairy platform, dairy support land used for wintering non-lactating cows (where applicable) and replacement stock, and imported supplements. Nitrate leaching was also estimated for the support land and growing of supplements imported from off-farm using the same methods as for the platform. Operating profit (NZ$/ha/year), nitrate leaching (kg N/ha/year), and greenhouse gas emissions (t CO2-equivalent/ha/year) were all expressed per hectare of milking platform to enable comparisons across regions. Nitrate leaching mitigations adopted in lower-input (less purchased feed and nitrogen fertiliser) farm systems reduced leaching by 22 to 30 per cent, and greenhouse gas emissions by between nine and 24 per cent. The exception was the wintering barn system in Otago, where nitrate leaching was reduced by 45 per cent, but greenhouse gas emissions were unchanged due to greater manure storage and handling. Important drivers of a lower environmental footprint are reducing nitrogen fertiliser and purchased feed. Their effect is to reduce feed flow through the herd and drive down both greenhouse gas emissions and nitrate leaching. Emission reductions in the lower-input systems of Waikato and Canterbury came at an average loss of profit of approximately NZ$100/t CO2-equivalent (three to five per cent of industry-average profit per hectare).
Publisher: Research Square Platform LLC
Date: 07-05-2021
DOI: 10.21203/RS.3.RS-481805/V1
Abstract: Background: Active crosstalk between the nervous system and breast cancer cells as well as other cell types within the tumour microenvironment has been experimentally demonstrated in vitro and in animal models. However, low frequencies of peripheral nerve presence in human breast cancers reported in previous studies (~30% of cases) potentially negate a major role of the nervous system in breast cancer development and progression. This study aimed to better define the incidence of nerves within human breast cancers and to delineate associations with clinicopathological features. Methods : Immunohistochemical staining was conducted in formalin-fixed paraffin-embedded breast cancer tissue sections using antibodies against the pan-neuronal markers protein gene product 9.5 (PGP9.5) and growth-associated protein 43 (GAP-43), and the sympathetic nerve-specific marker tyrosine hydroxylase (TH). Nerve trunks (comprised of many nerve fibres/axons) and isolated nerve fibres (positively stained cells with or without typical morphology of axons outside definable nerve trunks) were quantitated. The chi-squared test was used to determine the associations between nerve trunk or isolated nerve fibre counts and clinicopathological parameters. The Log-rank test was used to compare differences in patient progression-free survival (PFS) and overall survival (OS). A multivariate analysis was performed according to the Cox Proportional Hazards Model to assess independent prognostic factors. Results : Nerve trunks and isolated nerve fibres were detected in 75% and 77% of breast cancers, respectively. The overall frequency of peripheral nerves in breast cancers was 85%, a markedly higher proportion than reported previously. Of note, most nerves present in breast cancers were of the sympathetic origin (positive for TH). While high density of nerve trunks or isolated nerve fibres was associated with poor PFS and OS of patients, high nerve trunk density appeared also to predict poor patient PFS independently of lymph node metastasis. Conclusions: Innervation of breast cancers is a common event correlated with poor patient outcomes. These findings support the notion that the nervous system plays an active role in breast cancer pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2019
DOI: 10.1038/S41467-019-11132-W
Abstract: Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2012
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.JID.2016.06.625
Abstract: The effect of MTH1 inhibition on cancer cell survival has been elusive. Here we report that although silencing of MTH1 does not affect survival of melanoma cells, TH588, one of the first-in-class MTH1 inhibitors, kills melanoma cells through apoptosis independently of its inhibitory effect on MTH1. Induction of apoptosis by TH588 was not alleviated by MTH1 overexpression or introduction of the bacterial homolog of MTH1 that has 8-oxodGTPase activity but cannot be inhibited by TH588, indicating that MTH1 inhibition is not the cause of TH588-induced killing of melanoma cells. Although knockdown of MTH1 did not impinge on the viability of melanoma cells, it rendered melanoma cells sensitive to apoptosis induced by the oxidative stress inducer elesclomol. Of note, treatment with elesclomol also enhanced TH588-induced apoptosis, whereas a reactive oxygen species scavenger or an antioxidant attenuated the apoptosis triggered by TH588. Indeed, the sensitivity of melanoma cells to TH588 was correlated with endogenous levels of reactive oxygen species. Collectively, these results indicate that the cytotoxicity of TH588 toward melanoma cells is not associated with its inhibitory effect on MTH1, although it is mediated by cellular production of ROS.
Publisher: Wiley
Date: 14-11-2018
DOI: 10.1002/MC.22755
Abstract: Past studies have shown that mutant KRAS colon cancer cells are susceptible to apoptosis induced by the HSP90 inhibitor AUY922. Nevertheless, intrinsic and acquired resistance remains an obstacle for the potential application of the inhibitor in the treatment of the disease. Here we report that Mcl-1 is important for survival of colon cancer cells in the presence of AUY922. Mcl-1 was upregulated in mutant KRAS colon cancer cells selected for resistance to AUY922-induced apoptosis. This was due to its increased stability mediated by Bcl-2-associated athanogene domain 3 (BAG3), which was also increased in resistant colon cancer cells by heat shock factor 1 (HSF1) as a result of chronic endoplasmic reticulum (ER) stress. Functional investigations demonstrated that inhibition of Mcl-1, BAG3, or HSF1 triggered apoptosis in resistant colon cancer cells, and rendered AUY922-naïve colon cancer cells more sensitive to the inhibitor. Together, these results identify that the HSF1-BAG3-Mcl-1 signal axis is critical for protection of mutant KRAS colon cancer cells from AUY922-induced apoptosis, with potential implications for targeting HSF1/BAG3/Mcl-1 to improve the efficacy of AUY922 in the treatment of colon cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479852
Abstract: Supplementary Figure S1. TERT induces TERT-rearranged neuroblastoma cell proliferation and cell cycle progression through a telomerase-independent mechanism.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530307
Abstract: AbstractPurpose: i TERT /i gene rearrangement with transcriptional superenhancers leads to i TERT /i overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with i TERT /i -rearranged neuroblastoma. Experimental Design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with i TERT /i -rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. Results: The BET bromodomain protein BRD4 promoted i TERT /i -rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced i TERT /i -rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with i TERT /i -rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with i TERT /i -rearranged neuroblastoma. /
Publisher: Springer Science and Business Media LLC
Date: 28-03-2018
DOI: 10.1038/S41556-018-0066-7
Abstract: The list of long non-coding RNAs (lncRNAs) involved in the p53 pathway of the DNA damage response is rapidly expanding, but whether lncRNAs have a role in maintaining the de novo structure of DNA is unknown. Here, we demonstrate that the p53-responsive lncRNA GUARDIN is important for maintaining genomic integrity under steady-state conditions and after exposure to exogenous genotoxic stress. GUARDIN is necessary for preventing chromosome end-to-end fusion through maintaining the expression of telomeric repeat-binding factor 2 (TRF2) by sequestering microRNA-23a. Moreover, GUARDIN also sustains breast cancer 1 (BRCA1) stability by acting as an RNA scaffold to facilitate the heterodimerization of BRCA1 and BRCA1-associated RING domain protein 1 (BARD1). As such, GUARDIN silencing triggered apoptosis and senescence, enhanced cytotoxicity of additional genotoxic stress and inhibited cancer xenograft growth. Thus, GUARDIN may constitute a target for cancer treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479849.V1
Abstract: Supplementary Figure S2. BRD4 is required for TERT expression and cell proliferation in TERT-rearranged neuroblastoma cells.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2013
DOI: 10.1158/1535-7163.MCT-13-0011
Abstract: Inhibitors of the mitogen-activated protein kinases (MAPK), BRAF, and MAP–ERK kinase (MEK) induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6 to 7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now show that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib, or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signaling, decrease in bromodeoxyuridine incorporation, and S-phase inhibition. This cytostatic effect was also associated with diminished levels of cyclin D1 and p-pRb. Two short-term melanoma cultures generated from resistant tumor biopsies also responded to MAPK inhibition, with comparable inhibitory changes in proliferation and MAPK signaling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy. Mol Cancer Ther 12(7) 1332–42. ©2013 AACR.
Publisher: MDPI AG
Date: 12-04-2022
DOI: 10.3390/IJMS23084260
Abstract: There is increasing evidence that nerve growth factor (NGF) and its receptors, the neurotrophic receptor tyrosine kinase 1 (NTRK1/TrkA), the common neurotrophin receptor (NGFR 75NTR) and the membrane receptor sortilin, participate in cancer growth. In melanoma, there have been some reports suggesting that NGF, TrkA and p75NTR are dysregulated, but the expression of the NGF precursor (proNGF) and its membrane receptor sortilin is unknown. In this study, we investigated the expression of NGF, proNGF, TrkA, p75NTR and sortilin by immunohistochemistry in a series of human tissue s les (n = 100), including non-cancerous nevi (n = 20), primary melanomas (n = 40), lymph node metastases (n = 20) and distant metastases (n = 20). Immunostaining was digitally quantified and revealed NGF and proNGF were expressed in all nevi and primary melanomas, and that the level of expression decreased from primary tumors to melanoma metastases (p = 0.0179 and p 0.0001, respectively). Interestingly, TrkA protein expression was high in nevi and thin primary tumors but was strongly downregulated in thick primary tumors (p 0.0001) and metastases (p 0.0001). While p75NTR and sortilin were both expressed in most nevi and melanomas, there was no significant difference in expression between them. Together, these results pointed to a downregulation of NGF/ProNGF and TrkA in melanoma, and thus did not provide evidence to support the use of anti-proNGF/NGF or anti-TrkA therapies in advanced and metastatic forms of melanoma.
Publisher: Bentham Science Publishers Ltd.
Date: 31-03-2014
DOI: 10.2174/0929867321666131129114742
Abstract: Epidemiological evidence has linked the development and progression of several cancers including melanoma with obesity. However, whether obesity impinges on responses of cancer cells to treatment remains less understood. Here we report that human adipocytes contribute to resistance of melanoma cells to various therapeutic agents. Exposure to media from adipocyte cultures (adipocyte media) increased cell proliferation and reduced sensitivity of melanoma cells to apoptosis induced by erse chemotherapeutic drugs, including the DNA-damaging drug cisplatin, the microtubuletargeting agent docetaxel, and the histone deacetylase inhibitor SAHA. This was associated with increased activation of PI3K/Akt and MEK/ERK signaling, and was attenuated by a PI3K or MEK inhibitor. The effect of adipocyte media on melanoma cells was, at least in part, due to the interaction between the adipokine leptin and its long form receptor OB-Rb, in that immunodepletion of leptin in adipocyte media or siRNA knockdown of OB-Rb in melanoma cells reversed the increase in Akt and ERK activation, enhancement in cell proliferation, and importantly, protection of melanoma cells against the drugs. In support, recombinant leptin partially recapitulated the effect of adipocyte media on melanoma cells. Of note, OB-Rb was increased on the surface of melanoma cells compared to melanocytes, whereas leptin short form receptors appeared to be suppressed post-transcriptionally, suggesting that OB-Rb was selectively upregulated in melanoma cells. Collectively, these results indicate that adipocytes contribute to the resistance of melanoma cells to chemotherapeutic drugs and agents targeting the PI3K/Akt and MEK/ERK pathways, and suggest that inhibition of the leptin/ OB-Rb system may be useful to improve the efficacy of multiple therapeutic approaches in the treatment of melanoma.
Publisher: BMJ
Date: 11-2005
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.CELLSIG.2013.11.008
Abstract: Apoptosis triggered by endoplasmic reticulum (ER) stress is associated with rapid attenuation of the IRE1α and ATF6 pathways but persistent activation of the PERK branch of the unfolded protein response (UPR) in cells. However, melanoma cells are largely resistant to ER stress-induced apoptosis, suggesting that the kinetics and durations of activation of the UPR pathways are deregulated in melanoma cells undergoing ER stress. We show here that the IRE1α and ATF6 pathways are sustained along with the PERK signaling in melanoma cells subjected to pharmacological ER stress, and that this is, at least in part, due to increased activation of the MEK/ERK pathway. In contrast to an initial increase followed by rapid reduction in activation of IRE1α and ATF6 signaling in control cells that were relatively sensitive to ER stress-induced apoptosis, activation of IRE1α and ATF6 by the pharmacological ER stress inducer tunicamycin (TM) or thapsigargin (TG) persisted in melanoma cells. On the other hand, the increase in PERK signaling lasted similarly in both types of cells. Sustained activation of IRE1α and ATF6 signaling played an important role in protecting melanoma cells from ER stress-induced apoptosis, as interruption of IRE1α or ATF6 rendered melanoma cells sensitive to apoptosis induced by TM or TG. Inhibition of MEK partially blocked IRE1α and ATF6 activation, suggesting that MEK/ERK signaling contributed to sustained activation of IRE1α and ATF6. Taken together, these results identify sustained activation of the IRE1α and ATF6 pathways of the UPR driven by the MEK/ERK pathway as an important protective mechanism against ER stress-induced apoptosis in melanoma cells.
Publisher: Proceedings of the National Academy of Sciences
Date: 06-09-2011
Abstract: The tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the DNA repair machinery to preserve the cell, or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. The gene encoding p53 frequently undergoes inactivating mutations in many human cancers, but WT p53 is often expressed at high levels in melanoma, which, as judged from the malignant nature of the disease, fails to act as an effective tumor suppressor. Here we show that p53 directly up-regulates microRNA-149* (miR-149*) that in turn targets glycogen synthase kinase-3α, resulting in increased expression of Mcl-1 and resistance to apoptosis in melanoma cells. Although deficiency in miR-149* undermined survival of melanoma cells and inhibited melanoma growth in a mouse xenograft model, elevated expression of miR-149* was found in fresh human metastatic melanoma isolates, which was associated with decreased glycogen synthase kinase-3α and increased Mcl-1. These results reveal a p53-dependent, miR-149*–mediated pathway that contributes to survival of melanoma cells, provides a rational explanation for the ineffectiveness of p53 to suppress melanoma, and identifies the expression of miR-149* as a mechanism involved in the increased expression of Mcl-1 in melanoma cells.
Publisher: Wiley
Date: 13-11-2015
DOI: 10.1111/PCMR.12326
Abstract: Targeting the sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) signalling axis is emerging as a promising strategy in the treatment of cancer. However, the effect of such an approach on survival of human melanoma cells remains less understood. Here, we show that the sphingosine analogue FTY720 that functionally antagonises S1PRs kills human melanoma cells through a mechanism involving the vacuolar H(+) -ATPase activity. Moreover, we demonstrate that FTY720-triggered cell death is characterized by features of necrosis and is not dependent on receptor-interacting protein kinase 1 or lysosome cathepsins, nor was it associated with the activation of protein phosphatase 2A. Instead, it is mediated by increased production of reactive oxygen species and is antagonized by activation of autophagy. Collectively, these results suggest that FTY720 and its analogues are promising candidates for further development as new therapeutic agents in the treatment of melanoma.
Publisher: Springer Science and Business Media LLC
Date: 14-10-2014
DOI: 10.1038/ONC.2013.420
Abstract: Akt is constitutively activated in up to 70% of human melanomas and has an important role in the pathogenesis of the disease. However, little is known about protein phosphatases that dephosphorylate and thereby inactivate it in melanoma cells. Here we report that suppression of pleckstrin homology domain and leucine-rich repeat Ser/Thr protein phosphatase 1 (PHLPP1) by DNA methylation promotes Akt activation and has an oncogenic role in melanoma. While it is commonly downregulated, overexpression of PHLPP1 reduces Akt activation and inhibits melanoma cell proliferation in vitro, and retards melanoma growth in a xenograft model. In contrast, knockdown of PHLPP1 increases Akt activation, enhances melanoma cell and melanocyte proliferation, and results in anchorage-independent growth of melanocytes. Suppression of PHLPP1 involves blockade of binding of the transcription factor Sp1 to the PHLPP1 promoter. Collectively, these results suggest that suppression of PHLPP1 by DNA methylation contributes to melanoma development and progression.
Publisher: Informa UK Limited
Date: 03-07-2015
Publisher: Springer Science and Business Media LLC
Date: 25-11-2019
DOI: 10.1038/S41467-019-13313-Z
Abstract: Protein products of the regenerating islet-derived ( REG ) gene family are important regulators of many cellular processes. Here we functionally characterise a non-protein coding product of the family, the long noncoding RNA (lncRNA) REG1CP that is transcribed from a DNA fragment at the family locus previously thought to be a pseudogene. REG1CP forms an RNA–DNA triplex with a homopurine stretch at the distal promoter of the REG3A gene, through which the DNA helicase FANCJ is tethered to the core promoter of REG3A where it unwinds double stranded DNA and facilitates a permissive state for glucocorticoid receptor α (GRα)-mediated REG3A transcription. As such, REG1CP promotes cancer cell proliferation and tumorigenicity and its upregulation is associated with poor outcome of patients. REG1CP is also transcriptionally inducible by GRα, indicative of feedforward regulation. These results reveal the function and regulation of REG1CP and suggest that REG1CP may constitute a target for cancer treatment.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2013
Abstract: Past studies have shown that histone deacetylase (HDAC) and mutant BRAF (v-Raf murine sarcoma viral oncogene homolog B1) inhibitors synergistically kill melanoma cells with activating mutations in BRAF. However, the mechanism(s) involved remains less understood. Here, we report that combinations of HDAC and BRAF inhibitors kill BRAF V600E melanoma cells by induction of necrosis. Cotreatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) or panobinostat (LBH589) and the BRAF inhibitor PLX4720 activated the caspase cascade, but caspases appeared dispensable for killing, in that inhibition of caspases did not invariably block induction of cell death. The majority of dying cells acquired propidium iodide positivity instantly when they became positive for Annexin V, suggesting induction of necrosis. This was supported by caspase-independent release of high-mobility group protein B1, and further consolidated by rupture of the plasma membrane and loss of nuclear and cytoplasmic contents, as manifested by transmission electron microscopic analysis. Of note, neither the necrosis inhibitor necrostatin-1 nor the small interference RNA (siRNA) knockdown of receptor-interacting protein kinase 3 (RIPK3) inhibited cell death, suggesting that RIPK1 and RIPK3 do not contribute to induction of necrosis by combinations of HDAC and BRAF inhibitors in BRAF V600E melanoma cells. Significantly, SAHA and the clinically available BRAF inhibitor vemurafenib cooperatively inhibited BRAF V600E melanoma xenograft growth in a mouse model even when caspase-3 was inhibited. Taken together, these results indicate that cotreatment with HDAC and BRAF inhibitors can bypass canonical cell death pathways to kill melanoma cells, which may be of therapeutic advantage in the treatment of melanoma.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.4161/AUTO.19496
Publisher: Springer Science and Business Media LLC
Date: 24-06-2013
DOI: 10.1038/ONC.2012.214
Publisher: Springer Science and Business Media LLC
Date: 05-10-2020
DOI: 10.1038/S41467-020-18735-8
Abstract: The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14 ARF in human and p19 ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst erse cancer types and is shown to support cell survival, ision and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.
Publisher: Wiley
Date: 22-12-2010
Publisher: Springer Science and Business Media LLC
Date: 30-04-2018
DOI: 10.1038/S41388-018-0260-X
Abstract: The actin crosslinking protein α-actinin-4 (ACTN4) is emerging as an important contributor to the pathogenesis of cancer. This has largely been attributed to its role in regulating cytoskeleton organization and its involvement in transcriptional regulation of gene expression. Here we report a novel function of ACTN4 as a scaffold necessary for stabilization of receptor-interacting protein kinase 1 (RIPK1) that we have recently found to be an oncogenic driver in melanoma. ACTN4 bound to RIPK1 and cellular inhibitor of apoptosis protein 1 (cIAP1) with its actin-binding domain at the N-terminus and the CaM-like domain at the C-terminus, respectively. This facilitated the physical association between RIPK1 and cIAP1 and was critical for stabilization of RIPK1 that in turn activated NF-κB. Functional investigations showed that silencing of ACTN4 suppressed melanoma cell proliferation and retarded melanoma xenograft growth. In contrast, overexpression of ACTN4 promoted melanocyte and melanoma cell proliferation and moreover, prompted melanocyte anchorage-independent growth. Of note, the expression of ACTN4 was transcriptionally activated by NF-κB. Taken together, our findings identify ACTN4 as an oncogenic regulator through driving a feedforward signaling axis of ACTN4-RIPK1-NF-κB, with potential implications for targeting ACTN4 in the treatment of melanoma.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2021
DOI: 10.1158/1078-0432.CCR-20-3044
Abstract: TERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma. Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.
Publisher: Research Square Platform LLC
Date: 29-03-2023
DOI: 10.21203/RS.3.RS-2743610/V1
Abstract: With the growing recognition of RNA modification as a hallmark of cancer, N 1 -methyladenosine (m 1 A) methylation has been reported as a key mechanism of post-transcriptional regulation. However, the molecular mechanisms underlying m 1 A modification in bladder cancer (BLCA) progression remain unclear. In the current study, we aimed to explore the role of m 1 A methylation in BLCA. We found that the expression of the m 1 A methyltransferase TRMT61A was significantly elevated in human BLCA tissues. TRMT61A inhibition attenuated BLCA cell proliferation, migration, and invasion in vitro and tumor growth in vivo . Mechanistically, transcriptional profiling identified heme oxygenase-2 (HMOX2) as an m 1 A modification target of TRMT61A, and HMOX2 mRNA m 1 A modifications were reduced in TRMT61A-deficient cells. TRMT61A promoted HMOX2 mRNA stabilization in a YTHDF1-dependent manner, and YTHDF1 knockdown decreased the stability of HMOX2 mRNA through an m 1 A modification-dependent mechanism, leading to the inhibition of tumor cell proliferation. Moreover, NF-κB was found to bind to the promoter region of TRMT61A and stimulate its expression. NF-κB activation also increased the nuclear translocation of TRMT61A. Together, our results demonstrate the oncogenic role of TRMT61A and the m 1 A modification-mediated NF-κB/TRMT61A/HMOX2 signaling pathway activation in BLCA, thus highlighting a novel therapeutic target for this disease.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2015
DOI: 10.1038/ONC.2015.361
Publisher: Impact Journals, LLC
Date: 30-10-2014
Publisher: Springer Science and Business Media LLC
Date: 29-08-2014
Publisher: Elsevier BV
Date: 10-2011
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2011
End Date: 2013
Funder: National Health and Medical Research Council
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