ORCID Profile
0000-0002-4991-8870
Current Organisations
Peter MacCallum Cancer Centre
,
University of Melbourne
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Publisher: American Association for Cancer Research (AACR)
Date: 04-2017
DOI: 10.1158/2159-8290.CD-16-0611
Abstract: Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies to circumvent resistance are required. Using in vitro and in vivo metabolic profiling of TNBC cells, we show that an increase in the abundance of pyrimidine nucleotides occurs in response to chemotherapy exposure. Mechanistically, elevation of pyrimidine nucleotides induced by chemotherapy is dependent on increased activity of the de novo pyrimidine synthesis pathway. Pharmacologic inhibition of de novo pyrimidine synthesis sensitizes TNBC cells to genotoxic chemotherapy agents by exacerbating DNA damage. Moreover, combined treatment with doxorubicin and leflunomide, a clinically approved inhibitor of the de novo pyrimidine synthesis pathway, induces regression of TNBC xenografts. Thus, the increase in pyrimidine nucleotide levels observed following chemotherapy exposure represents a metabolic vulnerability that can be exploited to enhance the efficacy of chemotherapy for the treatment of TNBC. Significance: The prognosis for patients with TNBC with residual disease after chemotherapy is poor. We find that chemotherapy agents induce adaptive reprogramming of de novo pyrimidine synthesis and show that this response can be exploited pharmacologically, using clinically approved inhibitors of de novo pyrimidine synthesis, to sensitize TNBC cells to chemotherapy. Cancer Discov 7(4) 391–9. ©2017 AACR. See related article by Mathur et al., p. 380. This article is highlighted in the In This Issue feature, p. 339
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540936
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.BCP.2008.08.021
Abstract: Thioredoxin reductase (TrxR) is a key selenoprotein antioxidant enzyme and a potential target for anti-cancer drugs. One potent inhibitor of TrxR is the gold (I) compound auranofin, which can trigger mitochondrial-dependent apoptosis pathways. The exact mechanism of apoptosis induction by auranofin is not yet clear, but there are indications that mitochondrial oxidative stress is a central event. We assessed the redox state of the peroxiredoxins (Prxs) in Jurkat T-lymphoma cells treated with auranofin, and found that mitochondrial Prx3 was considerably more sensitive to oxidation than the cytosolic Prx1 and 2, indicating selective mitochondrial stress. Prx3 oxidation was detected at apoptotic doses of auranofin in several cell types, and occurred before other mitochondrial events including cytochrome c release and mitochondrial depolarisation. Auranofin was also able to sensitise U937 cells to TNF-alpha-mediated apoptosis. Auranofin-induced apoptosis was effectively blocked by the overexpression of Bcl-2, and Bax/Bak deficient mouse embryonic fibroblasts were also resistant to apoptosis, indicating a central role for the pro-apoptotic proteins of this family in auranofin-triggered apoptosis. Auranofin exposure inhibited the proliferation of apoptosis-resistant cells, and at higher doses of auranofin could cause cell death through necrosis. We conclude that auranofin induces apoptosis in cells through a Bax/Bak-dependent mechanism associated with selective disruption of mitochondrial redox homeostasis in conjunction with oxidation of Prx3.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540933
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Humana Press
Date: 2009
DOI: 10.1007/978-1-59745-281-6_23
Abstract: The oxidation and reduction of cysteine residues is emerging as an important post-translational control of protein function. We describe a method for fluorescent labelling of either reduced or oxidized thiols in combination with two-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis (2DE) to detect changes in the redox proteome of cultured cells. Reduced thiols are labelled with the fluorescent compound 5-iodoacetamidofluorescein. To monitor oxidized thiols, the reduced thiols are first blocked with N-ethyl-maleimide, then the oxidized thiols reduced with dithiothreitol and labelled with 5-iodoacetamidofluorescein. The method is illustrated by treating Jurkat T-lymphoma cells with hydrogen peroxide and monitoring increased labelling of oxidized thiol proteins. A decrease in labelling can also be detected, and this is attributed to the formation of higher oxidation states of cysteine that are not reduced by dithiothreitol.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540939
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540948.V1
Abstract: Supplementary Data from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 11-2009
Publisher: Elsevier BV
Date: 15-08-2008
DOI: 10.1016/J.FREERADBIOMED.2008.04.030
Abstract: Isothiocyanates are phytochemicals with anti-cancer properties that include the ability to trigger apoptosis. A substantial body of evidence suggests that reaction of the electrophilic isothiocyanate moiety with cysteine residues in cellular proteins and glutathione accounts for their biological activity. In this study we investigated the effect of several different isothiocyanates on the redox states of the cysteine-dependent peroxiredoxins (Prx) in Jurkat T lymphoma cells, and compared this to known effects on the selenoprotein thioredoxin reductase, glutathione reductase and intracellular GSH levels. Interestingly, oxidation of mitochondrial Prx3 could be detected as early as 5 min after exposure of cells to phenethyl isothiocyanate, with complete oxidation occurring at doses that only had small inhibitory effects on total cellular thioredoxin reductase and glutathione reductase activities. Peroxiredoxin oxidation was specific to the mitochondrial isoform with cytoplasmic Prx1 and Prx2 maintained in their reduced forms at all analyzed time points and concentrations of isothiocyanate. Phenethyl isothiocyanate could react with purified Prx3 directly, but it did not oxidize Prx3 or promote its oxidation by hydrogen peroxide. A selection of aromatic and alkyl isothiocyanates were tested and while all lowered cellular GSH levels, only the isothiocyanates that caused Prx3 oxidation were able to trigger cell death. We propose that pro-apoptotic isothiocyanates selectively disrupt mitochondrial redox homeostasis, as indicated by Prx3 oxidation, and that this contributes to their pro-apoptotic activity.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22495219
Abstract: Supplementary Table 1: Correlation coefficients and P values of metabolic rates and ssGSEA score. Supplementary Table 2: Correlation coefficients and P values of metabolic rates and genetic mutations. Supplementary Table 3: Correlation coefficients and P values of metabolic rates and copy number changes. Supplementary Table 4: Correlation coefficients and P values of metabolic rates and patient pre-treatments.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540930
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22495219.V1
Abstract: Supplementary Table 1: Correlation coefficients and P values of metabolic rates and ssGSEA score. Supplementary Table 2: Correlation coefficients and P values of metabolic rates and genetic mutations. Supplementary Table 3: Correlation coefficients and P values of metabolic rates and copy number changes. Supplementary Table 4: Correlation coefficients and P values of metabolic rates and patient pre-treatments.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540939.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 05-1995
DOI: 10.1016/S0968-0004(00)89007-6
Abstract: The discovery of structural and functional similarities between the product of the nematode cell-death gene ced-3 and mammalian interleukin-1 beta-converting enzyme (ICE) is providing important insights into the molecular mechanism of apoptosis. This article summarizes the current knowledge of ICE and its homologues, and how these may be involved in regulating apoptosis.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2012
DOI: 10.1038/NATURE11154
Publisher: Springer Science and Business Media LLC
Date: 18-07-2016
DOI: 10.1038/NCB3389
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540921.V1
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Proceedings of the National Academy of Sciences
Date: 09-2016
Abstract: Dietary selenium and selenoproteins play important roles in regulating redox processes that impact human health. The human genome includes 25 genes for selenoproteins, which have erse roles in redox homeostasis, thyroid hormone metabolism, endoplasmic reticulum quality control, selenium transport, and other functions. Selenoprotein H ( seph ) is a recently identified nucleolar oxidoreductase with DNA-binding properties whose function is not well understood. In this work, we used a unique combination of unbiased metabolomic and transcriptomic approaches in zebrafish to discover that seph is an essential regulator of redox homeostasis that regulates p53. In addition, we demonstrate the seph -deficient adults are prone to chemically induced carcinogenesis. Our results suggest that seph suppresses oxidative stress and DNA damage in the nucleolus.
Publisher: EMBO
Date: 28-09-2021
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540945
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540948
Abstract: Supplementary Data from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 06-2015
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549508
Abstract: Abstract Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked i in vitro /i and i in vivo /i synergy with venetoclax and overcomes venetoclax resistance in primary patient s les. Significance: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. i This article is highlighted in the In This Issue feature, p. 587 /i /
Publisher: Springer Science and Business Media LLC
Date: 18-07-2022
DOI: 10.1038/S41388-022-02408-5
Abstract: Glutamine is a conditionally essential nutrient for many cancer cells, but it remains unclear how consuming glutamine in excess of growth requirements confers greater fitness to glutamine-addicted cancers. By contrasting two breast cancer subtypes with distinct glutamine dependencies, we show that glutamine-indispensable triple-negative breast cancer (TNBC) cells rely on a non-canonical glutamine-to-glutamate overflow, with glutamine carbon routed once through the TCA cycle. Importantly, this single-pass glutaminolysis increases TCA cycle fluxes and replenishes TCA cycle intermediates in TNBC cells, a process that achieves net oxidation of glucose but not glutamine. The coupling of glucose and glutamine catabolism appears hard-wired via a distinct TNBC gene expression profile biased to strip and then sequester glutamine nitrogen, but h ers the ability of TNBC cells to oxidise glucose when glutamine is limiting. Our results provide a new understanding of how metabolically rigid TNBC cells are sensitive to glutamine deprivation and a way to select vulnerable TNBC subtypes that may be responsive to metabolic-targeted therapies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540942
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Faculty Opinions Ltd
Date: 03-02-2015
DOI: 10.12703/P7-13
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540915.V1
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Proceedings of the National Academy of Sciences
Date: 22-05-2023
Abstract: The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress-induced transcription factor that plays a central role in the regulation of redox balance and cellular metabolism. Under homeostatic conditions, NRF2 is repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate that Keap1 deficiency induces Nrf2 activation and postdevelopmental lethality. Loss of viability is preceded by severe liver abnormalities characterized by an accumulation of lysosomes. Mechanistically, we demonstrate that loss of Keap1 promotes aberrant activation of transcription factor EB (TFEB)/transcription factor binding to IGHM Enhancer 3 (TFE3)-dependent lysosomal biogenesis. Importantly, we find that NRF2-dependent regulation of lysosomal biogenesis is cell autonomous and evolutionarily conserved. These studies identify a role for the KEAP1–NRF2 pathway in the regulation of lysosomal biogenesis and suggest that maintenance of lysosomal homeostasis is required during embryonic development.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.C.6534778.V1
Abstract: Abstract Cancer cells undergo metabolic reprogramming to meet increased bioenergetic demands. Studies in cells and mice have highlighted the importance of oxidative metabolism and lipogenesis in prostate cancer however, the metabolic landscape of human prostate cancer remains unclear. To address this knowledge gap, we performed radiometric ( sup /sup C) and stable ( sup /sup C) isotope tracing assays in precision-cut slices of patient-derived xenografts (PDX). Glucose, glutamine, and fatty acid oxidation was variably upregulated in malignant PDXs compared with benign PDXs. i De novo /i lipogenesis (DNL) and storage of free fatty acids into phospholipids and triacylglycerols were increased in malignant PDXs. There was no difference in substrate utilization between localized and metastatic PDXs and hierarchical clustering revealed marked metabolic heterogeneity across all PDXs. Mechanistically, glucose utilization was mediated by acetyl-CoA production rather than carboxylation of pyruvate, while glutamine entered the tricarboxylic acid cycle through transaminase reactions before being utilized via oxidative or reductive pathways. Blocking fatty acid uptake or fatty acid oxidation with pharmacologic inhibitors was sufficient to reduce cell viability in PDX-derived organoids, whereas blockade of DNL, or glucose or glutamine oxidation induced variable and limited therapeutic efficacy. These findings demonstrate that human prostate cancer, irrespective of disease stage, can effectively utilize all metabolic substrates, albeit with marked heterogeneity across tumors. We also confirm that fatty acid uptake and oxidation are targetable metabolic dependencies in human prostate cancer. Implications: Prostate cancer utilizes multiple substrates to fuel energy requirements, yet pharmacologic targeting of fatty acid uptake and oxidation reveals metabolic dependencies in localized and metastatic tumors. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540936.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 03-2022
DOI: 10.1158/2159-8290.CD-21-0522
Abstract: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540927.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540918
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540915
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540933.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 07-2006
DOI: 10.1158/0008-5472.CAN-05-3809
Abstract: Isothiocyanates are a class of naturally occuring chemopreventive agents known to be effective at triggering apoptosis. In this study, we show that whereas overexpression of the oncoprotein Bcl-2 renders Jurkat T-lymphoma cells resistant to a range of cytotoxic agents, phenethyl isothiocyanate is able to overcome the inhibitory action of Bcl-2 and trigger apoptosis. A 50-fold increase in Bcl-2 expression shifted the dose-response curve, with an increase in the phenethyl isothiocyanate LD50 from 7 to 15 μmol/L, but there was still a complete loss in cell viability at doses in excess of 20 μmol/L. At these concentrations, cytotoxicity was strongly associated with caspase activation, phosphatidylserine exposure, and morphologic changes characteristic of apoptosis. Cytotoxicity was inhibited by treatment of the cells with a broad-spectrum caspase inhibitor. A structure-activity analysis showed that the phenethyl and benzyl isothiocyanates were most effective at triggering apoptosis in cells overexpressing Bcl-2 whereas phenyl isothiocyanate and benzyl thiocyanate had no proapoptotic activity. Allyl isothiocyanate also had limited efficacy despite its ability to trigger apoptosis in the parental Jurkat cell line. From this information, we propose that isothiocyanates modify a key cysteine residue in an apoptosis regulatory protein and that the aromatic side chain facilitates access to the target site. An in-depth investigation of the cellular targets of the aromatic isothiocyanates is warranted.(Cancer Res 2006 66(13): 6772-7)
Publisher: American Association for Cancer Research (AACR)
Date: 27-12-2022
DOI: 10.1158/1541-7786.MCR-22-0796
Abstract: Prostate cancer utilizes multiple substrates to fuel energy requirements, yet pharmacologic targeting of fatty acid uptake and oxidation reveals metabolic dependencies in localized and metastatic tumors.
Publisher: EMBO
Date: 22-10-2018
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.C.6534778
Abstract: Abstract Cancer cells undergo metabolic reprogramming to meet increased bioenergetic demands. Studies in cells and mice have highlighted the importance of oxidative metabolism and lipogenesis in prostate cancer however, the metabolic landscape of human prostate cancer remains unclear. To address this knowledge gap, we performed radiometric ( sup /sup C) and stable ( sup /sup C) isotope tracing assays in precision-cut slices of patient-derived xenografts (PDX). Glucose, glutamine, and fatty acid oxidation was variably upregulated in malignant PDXs compared with benign PDXs. i De novo /i lipogenesis (DNL) and storage of free fatty acids into phospholipids and triacylglycerols were increased in malignant PDXs. There was no difference in substrate utilization between localized and metastatic PDXs and hierarchical clustering revealed marked metabolic heterogeneity across all PDXs. Mechanistically, glucose utilization was mediated by acetyl-CoA production rather than carboxylation of pyruvate, while glutamine entered the tricarboxylic acid cycle through transaminase reactions before being utilized via oxidative or reductive pathways. Blocking fatty acid uptake or fatty acid oxidation with pharmacologic inhibitors was sufficient to reduce cell viability in PDX-derived organoids, whereas blockade of DNL, or glucose or glutamine oxidation induced variable and limited therapeutic efficacy. These findings demonstrate that human prostate cancer, irrespective of disease stage, can effectively utilize all metabolic substrates, albeit with marked heterogeneity across tumors. We also confirm that fatty acid uptake and oxidation are targetable metabolic dependencies in human prostate cancer. Implications: Prostate cancer utilizes multiple substrates to fuel energy requirements, yet pharmacologic targeting of fatty acid uptake and oxidation reveals metabolic dependencies in localized and metastatic tumors. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540918.V1
Abstract: Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540942.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 09-2012
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.BBAGEN.2011.06.004
Abstract: Isothiocyanates are phytochemicals with a broad array of effects in biological systems. Bioactivity includes the stimulation of cellular antioxidant systems, induction of apoptosis and interference with cytokine production and activity. Epidemiological evidence and experimental studies indicate that naturally occurring isothiocyanates and synthetic derivatives have anti-cancer and anti-inflammatory properties. This review focuses on the molecular targets of isothiocyanates, and how target modification translates into a biological response. Isothiocyanates may mediate their effects via direct protein modification or indirectly by disruption of redox homeostasis and increased thiol oxidation. Some target proteins have been identified, but in-depth searches with new techniques are needed to reveal novel targets. Site-directed mutagenesis and isothiocyanate structure-activity relationships will assist in determining the biological significance of specific modifications. Target identification is important for rational drug design and exploiting the therapeutic potential of isothiocyanates. It also provides insight into the erse pathways that these compounds regulate.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540924
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.CANLET.2008.06.002
Abstract: Isothiocyanates are a class of phytochemicals able to induce apoptosis in numerous cells including Jurkat T-lymphoma cells overexpressing the oncoprotein Bcl-2. To test if isothiocyanates are also effective against other anti-apoptotic members of the Bcl-2 family we generated Jurkat cells stably overexpressing Bcl-X(L). Phenethyl isothiocyanate (PEITC) was cytotoxic to these cells, with an LD(50) ranging from 9 to 18 microM depending on the level of Bcl-X(L) expression. Apoptosis induction in response to PEITC was confirmed by caspase activation and phosphatidylserine exposure. Isothiocyanates specifically target cysteine residues, therefore we tested the hypothesis that PEITC directly impairs Bcl-2 and Bcl-X(L) activity by interacting with their conserved cysteine residues. Jurkat cells overexpressing double cysteine mutants of Bcl-2 were generated, but they remained sensitive to PEITC. We conclude that PEITC antagonizes the action of anti-apoptotic Bcl-2 family members via an indirect mechanism.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540930.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 12-01-2021
DOI: 10.1158/2159-8290.CD-20-0738
Abstract: FLT3-ITD mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine biosynthesis, thereby rendering FLT3-ITD–driven leukemias dependent upon serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-ITD–driven AMLs to chemotherapy. This article is highlighted in the In This Issue feature, p. 1307
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540924.V1
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22495225
Abstract: Supplementary Figure 1. Metabolic profiles of prostate cancer PDX across different pathology. Supplementary Figure 2. Percent labeling of glycolysis end products and TCA cycle intermediates following 4 hours ex vivo labelling of 13C substrates. Supplementary Figure 3. Mass isotopologue distribution of malate following glucose, glutamine, palmitate, and lactate tracing. Supplementary Figure 4. PDXOs responses following metabolic inhibitors treatment. Supplementary Figure 5. Organoids viability following 7 days treatments of metabolic inhibitors. Supplementary Figure 6. Dose responses of metabolic inhibitors treatment in PDXOs.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540927
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540921
Abstract: Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.DEVCEL.2022.02.004
Abstract: The coordinated regulation of growth control and metabolic pathways is required to meet the energetic and biosynthetic demands associated with proliferation. Emerging evidence suggests that the Hippo pathway effector Yes-associated protein 1 (YAP) reprograms cellular metabolism to meet the anabolic demands of growth, although the mechanisms involved are poorly understood. Here, we demonstrate that YAP co-opts the sterol regulatory element-binding protein (SREBP)-dependent lipogenic program to facilitate proliferation and tissue growth. Mechanistically, YAP stimulates de novo lipogenesis via mechanistic target of rapamcyin (mTOR) complex 1 (mTORC1) signaling and subsequent activation of SREBP. Importantly, YAP-dependent regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) is required to activate mTORC1/SREBP and stimulate de novo lipogenesis. We also find that the SREBP target genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD) are conditionally required to support YAP-dependent proliferation and tissue growth. These studies reveal that de novo lipogenesis is a metabolic vulnerability that can be targeted to disrupt YAP-dependent proliferation and tissue growth.
Publisher: Wiley
Date: 19-02-2010
DOI: 10.1016/J.FEBSLET.2010.02.042
Abstract: Mitochondrial peroxiredoxin 3 (Prx 3) is rapidly oxidized in cells exposed to phenethyl isothiocyanate (PEITC) and auranofin (AFN), but the mechanism of oxidation is unclear. Using HL-60 cells deplete of mitochondrial DNA we show that peroxiredoxin 3 oxidation and cytotoxicity requires a functional respiratory chain. Thioredoxin reductase (TrxR) could be inhibited by up to 90% by auranofin without direct oxidation of peroxiredoxin 3. However, inhibition of thioredoxin reductase promoted peroxiredoxin 3 oxidation and cytotoxicity in combination with phenethyl isothiocyanate or antimycin A. We conclude that rapid peroxiredoxin 3 oxidation occurs as a consequence of increased oxidant production from the mitochondrial respiratory chain.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-05-2018
DOI: 10.1126/SCIIMMUNOL.AAR3451
Abstract: Whole-genome CRISPR screens identify resistance to TNF-mediated killing by T and NK cells as a tumor immune evasion mechanism.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22540945.V1
Abstract: Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Publisher: Cold Spring Harbor Laboratory
Date: 27-05-2020
DOI: 10.1101/2020.05.26.116392
Abstract: Activating FMS-like tyrosine kinase 3 ( FLT3 ) mutations occur in approximately 30% of all acute myeloid leukaemias (AMLs) and are associated with poor prognosis. The limited clinical efficacy of FLT3 inhibitor monotherapy has highlighted the need for alternative therapeutic targets and treatments for FLT3-mutant AML. Using human and murine models of MLL-rearranged AML harbouring FLT3 internal tandem duplication (FLT3-ITD) and primary patient s les, we have demonstrated that FLT3-ITD promotes serine uptake and serine synthesis via transcriptional regulation of neutral amino acid transporters ( SLC1A4 and SLC1A5 ) and genes in the de novo serine synthesis pathway ( PHGDH and PSAT1 ). Mechanistically, dysregulation of serine metabolism in FLT3-mutant AML is dependent on the mTORC1-ATF4 axis, that drives RNA-Pol II occupancy at PHGDH, PSAT1, SLC1A4 and SLC1A5 . Genetic or pharmacological inhibition of the de novo serine synthesis pathway selectively inhibited the proliferation of FLT3-ITD AML cells, and this was potentiated by withdrawal of exogenous serine. Purine supplementation effectively rescued the antiproliferative effect of inhibiting de novo serine synthesis, consistent with the idea that serine fuels purine nucleotide synthesis in FLT3-mutant AML. Pharmacological inhibition of the de novo serine synthesis pathway, using the PHGDH inhibitor WQ-2101, sensitises FLT3-mutant AML cells to the standard of care chemotherapy agent cytarabine via exacerbation of DNA damage. Collectively, these data reveal new insights as to how FLT3 mutations reprogram metabolism in AML, and reveal a combination therapy strategy to improve the treatment of FLT3-mutant AML. FLT3 mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine metabolism, thereby rendering FLT3-ITD leukemias dependent on serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-mutant AML to chemotherapy.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1541-7786.22495225.V1
Abstract: Supplementary Figure 1. Metabolic profiles of prostate cancer PDX across different pathology. Supplementary Figure 2. Percent labeling of glycolysis end products and TCA cycle intermediates following 4 hours ex vivo labelling of 13C substrates. Supplementary Figure 3. Mass isotopologue distribution of malate following glucose, glutamine, palmitate, and lactate tracing. Supplementary Figure 4. PDXOs responses following metabolic inhibitors treatment. Supplementary Figure 5. Organoids viability following 7 days treatments of metabolic inhibitors. Supplementary Figure 6. Dose responses of metabolic inhibitors treatment in PDXOs.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549508.V1
Abstract: Abstract Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked i in vitro /i and i in vivo /i synergy with venetoclax and overcomes venetoclax resistance in primary patient s les. Significance: Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. i This article is highlighted in the In This Issue feature, p. 587 /i /
Publisher: Elsevier BV
Date: 2014
Location: United States of America
Start Date: 2021
End Date: 2023
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2021
Funder: Susan G. Komen Breast Cancer Foundation
View Funded ActivityStart Date: 2021
End Date: End date not available
Funder: National Health and Medical Research Council
View Funded Activity