ORCID Profile
0000-0001-6371-3751
Current Organisation
University of Technology Sydney
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Publisher: Wiley
Date: 11-11-2009
DOI: 10.1111/J.1349-7006.2009.01340.X
Abstract: Drug resistance is a major concern in the successful treatment of ovarian cancer. In the present study we report a combinational drug regime using arsenic trioxide (ATO) and cisplatin (CDDP) to increase therapeutic potentiality in ovarian cancer cells. ATO-mediated growth inhibition and apoptosis in human suspension ovarian cancer COC1 cells were evaluated by MTT assay and annexin V assay using flow cytometry, respectively. cDNA arrays were performed to screen ATO-mediated gene expression. Treatment of COC1 cells with ATO alone resulted in growth inhibition and apoptosis with a dose-and time-dependent fashion further cDNA arrays showed that 34 genes (23 up-regulated genes and 11 down-regulated genes) may strongly associate with the antiproliferative and pro-apoptotic effects induced by ATO. Furthermore, Chou-Talalay analysis was used to evaluate the combinational effect of ATO and CDDP as well as dose-reduction index (DRI) in a panel of ovarian cancer cells including CDDP-sensitive and -resistant cell lines. The combination index (CI) analysis indicated that the interaction effect of ATO/CDDP exhibited a wide range of synergism in all the adherent ovarian cancer cells (A2780, IGROV-1, SKOV-3, and R182) as well as 0.93 to 0.69 for IC(50) to IC(90) in suspension COC1 cells where CI 1, define synergism, additive effect, and antagonism, respectively. More intriguingly, the combination of ATO and CDDP yielded favorable DRIs ranging from 1.23-fold to 13.51-fold dose reduction. These results suggest that ATO and its combination with CDDP present therapeutic potential for ovarian cancer, and deserve further preclinical and clinical studies.
Publisher: The Endocrine Society
Date: 08-1999
Abstract: The human progesterone receptor (PR) is expressed as two isoforms, PRA and PRB, that function as ligand-activated transcription factors. In vitro studies suggest that the isoforms differ functionally and that the relative levels in a target cell may determine the nature and magnitude of response to progesterone. However, it is not known whether the two isoforms are normally coexpressed in vivo. To understand the functional significance of relative PR isoform expression in normal physiology, it is essential to determine whether PRA and PRB are coexpressed in the same cell. This study reports the development of a dual immunofluorescent staining technique to demonstrate PRA and PRB proteins by single cell analysis in the same tissue section of human endometrium during the menstrual cycle. PRA and PRB are coexpressed in target cells of the human uterus. In the glands, PRA and PRB were expressed before subnuclear vacuole formation and glycogenolysis, implicating both isoforms in this process, whereas persistence of PRB during the midsecretory phase suggested its significance in glandular secretion. In the stroma, the predominance of PRA throughout the cycle implicates this isoform in postovulatory progesterone-mediated events. These results support the view that PRA and PRB mediate distinct pathways of progesterone action in the glandular epithelium and stroma of the human uterus throughout the menstrual cycle.
Publisher: MDPI AG
Date: 15-02-2023
DOI: 10.3390/MD21020128
Abstract: Fucoidans, discovered in 1913, are fucose-rich sulfated polysaccharides extracted mainly from brown seaweed. These versatile and nontoxic marine-origin heteropolysaccharides have a wide range of favorable biological activities, including antitumor, immunomodulatory, antiviral, antithrombotic, anticoagulant, antithrombotic, antioxidant, and lipid-lowering activities. In the early 1980s, fucoidans were first recognized for their role in supporting the immune response and later, in the 1990s, their effects on immune potentiation began to emerge. In recent years, the understanding of the immunomodulatory effects of fucoidan has expanded significantly. The ability of fucoidan(s) to activate CTL-mediated cytotoxicity against cancer cells, strong antitumor property, and robust safety profile make fucoidans desirable for effective cancer immunotherapy. This review focusses on current progress and understanding of the immunopotentiation activity of various fucoidans, emphasizing their relevance to cancer immunotherapy. Here, we will discuss the action of fucoidans in different immune cells and review how fucoidans can be used as adjuvants in conjunction with immunotherapeutic products to improve cancer treatment and clinical outcome. Some key rationales for the possible combination of fucoidans with immunotherapy will be discussed. An update is provided on human clinical studies and available registered cancer clinical trials using fucoidans while highlighting future prospects and challenges.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2018
Publisher: Springer Science and Business Media LLC
Date: 19-02-2018
Publisher: Elsevier BV
Date: 09-2011
Publisher: Impact Journals, LLC
Date: 18-03-2017
Publisher: MDPI AG
Date: 08-06-2018
Publisher: Springer Science and Business Media LLC
Date: 09-1994
DOI: 10.1007/BF01309484
Publisher: Mary Ann Liebert Inc
Date: 02-2018
Abstract: Lung cancer, caused mainly by smoking, is one of the most prevalent diseases in China, resulting in high mortality rates. The increasing incidence of chronic disease due to lung cancer places a huge burden on the welfare and cost to the Chinese society. Amplification of the fibroblast growth factor receptor 1 (FGFR1) is associated with high incidence and mortality in lung cancer patients. FGFR1 signaling is implicated in oncogenic traits such as proliferation, cell survival, angiogenesis, and migration. Targeting FGFR1 and its ligand basic FGF (bFGF) is a key step forward in developing new therapies for this crippling disease. Lung adenocarcinoma is the most common subtype of non-small-cell lung cancer. In this study, A549, a lung adenocarcinoma cell line widely used in vitro as a model for drug metabolism and as a transfection host, was used to study FGFR1. A stable lentiviral FGFR1 over-expression system in lung cancer cells is described for the study of anti-lung cancer drug candidates targeting FGFR1. Ligand binding to FGFR1 activates the PI3K/Akt/mTOR signaling pathway and increases adhesion, invasion, and migration in this model. Using a unique FGF monoclonal antibody developed in the laboratory, the overactive PI3K pathway was effectively blocked, abrogating the negative metastatic signaling pathways in lung cancer cells. Importantly, this model provides an effective and simple screening kit for anti-FGF1 drug compounds for lung cancer treatment and a tool for understanding the molecular mechanisms of the FGFR1 signaling pathway in lung cancer. Furthermore, this toolkit based on a FGFR1 lentiviral construct model is transferrable to study FGFR1 signaling in any type of cancer cell.
Publisher: Frontiers Media SA
Date: 29-05-2019
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/548436
Abstract: There is substantial epidemiological evidence pointing to an increased incidence of breast cancer and morbidity in obese, prediabetic, and diabetic patients. In vitro studies strongly support metformin, a diabetic medication, in breast cancer therapy. Although metformin has been heralded as an exciting new breast cancer treatment, the principal consideration is whether metformin can be used as a generic treatment for all breast cancer types. Importantly, will metformin be useful as an inexpensive therapy for patients with comorbidity of diabetes and breast cancer? In general, meta-analyses of clinical trial data from retrospective studies in which metformin treatment has been used for patients with diabetes and breast cancer have a positive trend nevertheless, the supporting clinical data outcomes remain inconclusive. The heterogeneity of breast cancer, confounded by comorbidity of disease in the elderly population, makes it difficult to determine the actual benefits of metformin therapy. Despite the questionable evidence available from observational clinical studies and meta-analyses, randomized phases I–III clinical trials are ongoing to test the efficacy of metformin for breast cancer. This special issue review will focus on recent research, highlighting in vitro research and retrospective observational clinical studies and current clinical trials on metformin action in breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: Elsevier BV
Date: 09-2009
Publisher: MDPI AG
Date: 02-09-2017
DOI: 10.3390/IJMS18091891
Abstract: Sphingosine kinase (SphK) is a lipid enzyme that maintains cellular lipid homeostasis. Two SphK isozymes, SphK1 and SphK2, are expressed from different chromosomes and several variant isoforms are expressed from each of the isozymes, allowing for the multi-faceted biological ersity of SphK activity. Historically, SphK1 is mainly associated with oncogenicity, however in reality, both SphK1 and SphK2 isozymes possess oncogenic properties and are recognized therapeutic targets. The absence of mutations of SphK in various cancer types has led to the theory that cancer cells develop a dependency on SphK signaling (hyper-SphK signaling) or “non-oncogenic addiction”. Here we discuss additional theories of SphK cellular mislocation and aberrant “dicing and splicing” as contributors to cancer cell biology and as key determinants of the success or failure of SphK/S1P (sphingosine 1 phosphate) based therapeutics.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2017
Publisher: Elsevier BV
Date: 12-1995
Publisher: SAGE Publications
Date: 2018
Abstract: Cardiovascular disease (CVD) is the leading cause of death in the world and our approach to the control and management of CVD mortality is limited. Nattokinase (NK), the most active ingredient of natto, possesses a variety of favourable cardiovascular effects and the consumption of Natto has been linked to a reduction in CVD mortality. Recent research has demonstrated that NK has potent fibrinolytic activity, antihypertensive, anti-atherosclerotic, and lipid-lowering, antiplatelet, and neuroprotective effects. This review covers the major pharmacologic effects of NK with a focus on its clinical relevance to CVD. It outlines the advantages of NK and the outstanding issues pertaining to NK pharmacokinetics. Available evidence suggests that NK is a unique natural compound that possesses several key cardiovascular beneficial effects for patients with CVD and is therefore an ideal drug candidate for the prevention and treatment of CVD. Nattokinase is a promising alternative in the management of CVD.
Publisher: Springer Science and Business Media LLC
Date: 02-2004
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.JSBMB.2019.105560
Abstract: Progesterone receptor isoforms A and B exert different biological effects in breast cancer cells. Alteration of PRA/PRB ratio is often observed during breast cancer progression. High PRA/PRB ratios in breast cancer patients are associated with resistance to chemotherapy and poor prognosis. While it is well accepted that PRA and PRB regulate different sets of genes, how the expression of PRA and PRB alters breast cancer proteomes has not been fully investigated. To directly investigate the effects of PR isoform expression on the breast cancer proteome, both in the presence and absence of progestin, PRA and PRB were independently stably expressed in T47DC42 PR-null breast cancer cells using a doxycycline (Dox)-regulated promoter. Dox induction dose-dependently increased PRA and PRB expression. Dox-induced PRA and PRB showed normal receptor localization and were transcriptionally active. Differential quantitative proteomic analysis by stable isotope dimethyl labeling was performed to quantitatively examine how PR isoforms altered global breast cancer proteomes. Cells expressing PRA in the absence of progestin were enriched in proteins involved in the TCA cycle and enriched in proteins involved in glycolysis in the presence of progestin, whilst cells expressing PRB in the absence and presence progestin were significantly enriched in proteins involved in the cell cycle and cell apoptosis pathways. This proteomic data revealed a link between PR isoform expression and alteration in cell metabolism, cell proliferation, and apoptosis. The enrichment of proteins involved in the glycolytic pathway in breast cancer cells expressing PRA is consistent with stem cell-like properties, previously reported in PRA-rich breast cancer cells. Moreover, compared to liganded PRB, liganded PRA differentially upregulated proteins involved in chromatin remodeling, such as linker histone H1.2. Silencing H1.2 gene expression suppressed PRA-mediated cell proliferation and promoted G2/M and S phase entry of the cell cycle. Additionally, liganded PRA upregulated the expression of cathepsin D (CTSD) protease, whose expression is associated with poor prognosis in breast cancer patients. Together, our data demonstrated that the expression of PRA or PRB dramatically and differentially altered breast cancer cell proteomes. These isoform-specific changes in the breast cancer proteome will help to explain the distinct phenotypic properties of breast cancer cells expressing different levels of PRA and PRB.
Publisher: Baishideng Publishing Group Inc.
Date: 21-01-2019
Publisher: American Association for Cancer Research (AACR)
Date: 12-2010
DOI: 10.1158/0008-5472.SABCS10-P1-04-03
Abstract: Many years of oncogenic insult and hormonal flux have important long-term implications for breast cancer emergence and progression. Premature-induced senescence is proposed to be a protective response against cancer development. We hypothesize that the senescence response can be subverted in some breast carcinomas, which exhibit latent hormone-dependent proliferative capacity. The ARF-p53 pathway has long been known to play an important role in tumour surveillance halting cell cycle progression to transiently or permanently stop aberrant cells from proliferating. It is well documented that disruption of this pathway is involved in tumourigenesis, in part, through inactivation of cyclin D1. Cyclin D1 plays an important role in breast cancer progression as a regulator of CDK4/6. In addition cyclin D1 has been reported to stimulate estrogen receptor (ER) activity independent of CDK4/6. Our initial observations showed that reactivation of ARF-p53-p21 is indeed a potent rapid inhibitor of cell proliferation in MCF-7 breast cancer cells with a senescent phenotype, however controversially cyclin D1 expression was increased and predominantly located in the nucleus. High expression of nuclear cyclin D1 and p14ARF inversely correlated with cell proliferation. Our studies showed that p14ARF regulated cyclin D1 at the post-transcriptional level. Furthermore, we have evidence from microRNA array analysis that microRNAs known to bind to the cyclin D1 3'UTR sequence were down regulated upon induction of p14ARF, contributing to cyclin D1 stability. We found that long-term exposure to p14ARF was not a failsafe barrier to tumour progression, senescent-like cells re-entering the cell cycle correlated with reduction of nuclear cyclin D1. Conversely, continuous p14ARF expression resulted in chaotic multinucleation and preceded neoplasia. These aberrant nuclei co-stained with cyclin D1 and Ki-67, a well-known marker of cell proliferation. These results suggest that induction of the p14ARF-p53 pathway does not entirely remove the threat of cancer resulting from hyperproliferative oncogenic signals and cyclin D1 plays a promiscuous role in prevention and progression. Arguably, in some breast cancers premature senescent cells may be precursor, or latent cancer cells. Citation Information: Cancer Res 2010 (24 Suppl):Abstract nr P1-04-03.
Publisher: MDPI AG
Date: 12-10-2023
Publisher: The Endocrine Society
Date: 02-2007
DOI: 10.1210/ME.2006-0337
Abstract: Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. Progestin activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. Progestin induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src. Progestin induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/165105
Abstract: Cancer and diabetes are among the most common diseases in western societies. Epidemiological studies have shown that diabetic patients have a significantly higher risk of developing a number of different types of cancers and that in iduals with comorbidity (cancer and diabetes rediabetes) have a poorer prognosis relative to nondiabetic cancer patients. The increasing frequency of comorbidity of cancer and diabetes mellitus, mainly type 2 diabetes, has driven the development of therapeutic interventions that target both disease states. There is strong evidence to suggest that balancing the sphingolipid rheostat, ceramide—sphingosine—sphingosine-1-phosphate (S1P) is crucial in the prevention of diabetes and cancer and sphingosine kinase/S1P modulators are currently under development for the treatment of cancer and diabetes. This paper will highlight some of the complexities inherent in the use of the emerging sphingosine kinase/S1P modulators in the treatment of comorbidity of diabetes and cancer.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/386203
Publisher: Humana Press
Date: 2000
Publisher: The Endocrine Society
Date: 08-1999
DOI: 10.1210/JC.84.8.2963
Publisher: Oxford University Press (OUP)
Date: 08-2000
DOI: 10.1093/HUMREP/15.SUPPL_3.48
Abstract: The human progesterone receptor (PR) is expressed as two isoforms, PRA and PRB, which function as ligand-activated transcription factors. In-vitro studies suggest that the isoforms differ functionally and that their relative expression in a target cell may determine the nature and magnitude of response to progesterone. We have shown recently that PRA and PRB are co-expressed in target cells of the human endometrium. The purpose of this study was to investigate the homogeneity of expression of PRA and PRB in target cells of the human uterus throughout the menstrual cycle. In the functionalis, PRA and PRB were expressed in comparable levels in glandular epithelium during the proliferative phase of the cycle, whereas there was persistence of PRB but not PRA in the glands during mid-secretory phase. In the stroma, there was predominance of the PRA isoform throughout the cycle. There was remarkable homogeneity in the relative expression of PRA and PRB in adjacent cells within the same tissue compartment, suggesting that the mechanisms regulating relative PR isoform expression are similarly active in these cells. By contrast, heterogeneity between glands was observed under some circumstances in the functionalis of the endometrium, suggesting PR isoform down-regulation by progesterone to be asynchronous. Heterogeneity was also seen between the glands of the basalis and functionalis of the endometrium implying region-specific responses to hormonal stimuli. This study demonstrates adjacent cell homogeneity in the relative expression of PRA and PRB in normal human endometrial tissue and a differential response to ovarian steroid hormones between cell types and between different regions within the same tissue.
Publisher: MDPI AG
Date: 29-09-2020
DOI: 10.3390/IJMS21197189
Abstract: The world is currently experiencing the worst health pandemic since the Spanish flu in 1918—the COVID-19 pandemic—caused by the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic is the world’s third wake-up call this century. In 2003 and 2012, the world experienced two major coronavirus outbreaks, SARS-CoV-1 and Middle East Respiratory syndrome coronavirus (MERS-CoV), causing major respiratory tract infections. At present, there is neither a vaccine nor a cure for COVID-19. The severe COVID-19 symptoms of hyperinflammation, catastrophic damage to the vascular endothelium, thrombotic complications, septic shock, brain damage, acute disseminated encephalomyelitis (ADEM), and acute neurological and psychiatric complications are unprecedented. Many COVID-19 deaths result from the aftermath of hyperinflammatory complications, also referred to as the “cytokine storm syndrome”, endotheliitus and blood clotting, all with the potential to cause multiorgan dysfunction. The sphingolipid rheostat plays integral roles in viral replication, activation/modulation of the immune response, and importantly in maintaining vasculature integrity, with sphingosine 1 phosphate (S1P) and its cognate receptors (SIPRs: G-protein-coupled receptors) being key factors in vascular protection against endotheliitus. Hence, modulation of sphingosine kinase (SphK), S1P, and the S1P receptor pathway may provide significant beneficial effects towards counteracting the life-threatening, acute, and chronic complications associated with SARS-CoV-2 infection. This review provides a comprehensive overview of SARS-CoV-2 infection and disease, prospective vaccines, and current treatments. We then discuss the evidence supporting the targeting of SphK/S1P and S1P receptors in the repertoire of COVID-19 therapies to control viral replication and alleviate the known and emerging acute and chronic symptoms of COVID-19. Three clinical trials using FDA-approved sphingolipid-based drugs being repurposed and evaluated to help in alleviating COVID-19 symptoms are discussed.
Publisher: Hindawi Limited
Date: 07-12-2022
DOI: 10.1155/2022/2250407
Abstract: Background.Overexpression of sphingosine kinase 1 (SphK1) is casually associated with many types of cancer, and inhibitors of SphK1 sensitize tumors to chemotherapy. SphK1 is expressed as two major isoforms, SphK1a and SphK1b. To date, no information has been reported on the SphK1 isoform expression profile and its clinical relevance. Objective. The objective is to examine the expression profile of the SphK1a and SPhK1b isoforms in human cancer and noncancer tissues and cell lines and explore their clinical relevance. Methods. We used PCR to qualitatively examine the expression profile of these two isoforms in breast, liver, and prostate cancer tissues plus paired adjacent tissues and in 11 cancer and normal cell lines (breast, cervical, bone, prostate, colon, brain, mesothelioma tumor and benign, and human kidney cells). Results. We found that SphK1a was ubiquitously expressed in all cancer cells and tissues tested in contrast, SphK1b was only expressed in selective cell types in breast, prostate, and lung cancer. Conclusions. Our data suggest that SphK1a is important for generic SphK1/S1P functions, and SphK1b mediates specialized and/or unique pathways in a specific type of tissue and could be a biomarker for cancer. This discovery is important for future SphK1-related cancer research and may have clinical implications in drug development associated with SphK1-directed cancer treatment.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.BIOPHA.2019.109625
Abstract: Unprecedented efficacy of chimeric antigen receptor (CAR) T cell therapy in the treatment of hematologic malignancies brings new hope for patients with many cancer types including solid tumors. However, the challenges for CAR-T cell therapy in eradicating solid tumors are immense. To overcome these seemingly intractable hurdles, more "powerful" CAR-T cells with enhanced antitumor efficacy are required. Emerging data support that the anti-tumor activity of CAR-T cells can be enhanced significantly without evident toxicity through simultaneous PD-1 disruption by genome editing. This review focuses on the current progress of PD-1 gene disrupted CAR-T cells in cancer therapy. Here we discuss key rationales for this new combination strategy and summarize the available pre-clinical studies. An update is provided on human clinical studies and available registered cancer clinical trials using CAR-T cells with PD-1 disruption. Future prospects and challenges are also discussed.
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2007
DOI: 10.1158/0008-5472.CAN-07-1255
Abstract: Estrogen treatment of MCF-7 human breast cancer cells allows the reinitiation of synchronous cell cycle progression in antiestrogen-arrested cells. Here, we report that progestins also reinitiate cell cycle progression in this model. Using clonal cell lines derived from progesterone receptor (PR)–negative MCF-7M13 cells expressing wild-type or mutant forms of PRA and PRB, we show that this effect is mediated via PRB, not PRA. Cell cycle progression did not occur with a DNA-binding domain mutant of PRB but was unaffected by mutation in the NH2-terminal, SH3 domain interaction motif, which mediates rapid progestin activation of c-Src. Thus, the progestin-induced proliferative response in antiestrogen-inhibited cells is mediated primarily by the transcriptional activity of PRB. Analysis of selected cell cycle targets showed that progestin treatment induced levels of cyclin D1 expression and retinoblastoma protein (Rb) phosphorylation similar to those induced by estradiol. In contrast, progestin treatment resulted in only a 1.2-fold induction of c-Myc compared with a 10-fold induction by estradiol. These results support the conclusion that progestin, in a PRB-dependent manner, can overcome the growth-inhibitory effects of antiestrogens in estrogen receptor/PR-positive breast cancer cells by the induction of cyclin D1 expression. The mediation of this effect by PRB, but not PRA, further suggests a mechanism whereby abnormal regulation of the normal expression ratios of PR isoforms in breast cancer could lead to the attenuation of antiestrogen-mediated growth arrest. [Cancer Res 2007 (18):8942–51]
Publisher: MDPI AG
Date: 21-01-2022
Abstract: Incidence of gastrointestinal (GI) cancers is increasing, and late-stage diagnosis makes these cancers difficult to treat. Chronic and low-grade inflammation are recognized risks for most GI cancers. The GI mucosal immune system maintains healthy homeostasis and signalling molecules made from saturated fats, bioactive sphingolipids, play essential roles in healthy GI immunity. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, is a key mediator in a balanced GI immune response. Disruption in the S1P pathway underlies systemic chronic metabolic inflammatory disorders, including diabetes and GI cancers, providing a strong rationale for using modulators of the S1P pathway to treat pathological inflammation. Here, we discuss the effects of bioactive sphingolipids in immune homeostasis with a focus on S1P in chronic low-grade inflammation associated with increased risk of GI carcinogenesis. Contemporary information on S1P signalling involvement in cancers of the digestive system, from top to bottom, is reviewed. Further, we discuss the use of novel S1P receptor modulators currently in clinical trials and their potential as first-line drugs in the clinic for chronic inflammatory diseases. Recently, ozanimod (ZeposiaTM) and etrasimod have been approved for clinical use to treat ulcerative colitis and eosinophilic oesophagitis, respectively, which may have longer term benefits in reducing risk of GI cancers.
Publisher: Elsevier
Date: 2020
Publisher: Bioscientifica
Date: 10-2003
Abstract: Changes in the cell cytoskeleton occur in cell transformation and recent data suggest the involvement of ovarian hormones, which are implicated in cancer development and progression. In human breast and endometrial tumors, there is disrupted expression of progesterone receptor (PR) isoforms and predominance of one isoform, usually PRA. PRA predominance is an early event in carcinogenesis, and in cancers is associated with poor clinical features. Overexpression of PRA in vitro causes altered progestin regulation of cell morphology, suggesting that PRA overexpression may provoke deleterious changes in cell functioning. This study aimed to identify pathways of cytoskeleton regulation responsive to progestins and to determine whether these are perturbed when PRA is overexpressed to the levels seen in cancers. Progestin treatment of PR-positive breast cancer cells caused increased cell surface area whereas after induction of a stably integrated PRA construct, cells became rounded and the cell surface was decreased. The effect of PRA induction on cell rounding was reversed by the anti-progestin RU38486. Altered tropomyosin (Tm) isoforms were implicated in these morphological differences, as there was a PRA-mediated alteration in Tm5 isoform levels, and transfection of Tm5a mimicked progestin-mediated cell rounding in PRA-overexpressing cells. Ezrin was redistributed from the membrane to cytoplasmic locations in the presence of progestin, and discrete focal localization was evident in cells with PRA predominance. Progestin effects on the cytoskeleton in PRA-overexpressing cells provide evidence for novel endocrine regulation of aspects of actin microfilament composition, suggesting that changes in the cytoskeleton known to be associated with cancer development and progression may be regulated in part by altered PRA expression which develops early in carcinogenesis.
Publisher: Public Library of Science (PLoS)
Date: 14-07-2016
Publisher: Public Library of Science (PLoS)
Date: 09-01-2017
Publisher: MDPI AG
Date: 31-05-2018
Publisher: Elsevier BV
Date: 05-2018
Location: United States of America
No related grants have been discovered for Eileen McGowan.