Dataset Information

PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers.

ABSTRACT: High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOCs rely on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1? axis in the metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-activator PGC-1?. Active PGC-1? increases synthesis of electron transport chain complexes, thereby promoting mitochondrial respiration. Importantly, high-OXPHOS HGSOCs exhibit increased response to conventional chemotherapies, in which increased oxidative stress, PML, and potentially ferroptosis play key functions. Collectively, our data establish a stress-mediated PML-PGC-1?-dependent mechanism that promotes OXPHOS metabolism and chemosensitivity in ovarian cancer.

SUBMITTER: Gentric G

PROVIDER: S-EPMC6331342 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers.

Gentric Géraldine G Kieffer Yann Y Mieulet Virginie V Goundiam Oumou O Bonneau Claire C Nemati Fariba F Hurbain Ilse I Raposo Graca G Popova Tatiana T Stern Marc-Henri MH Lallemand-Breitenbach Valérie V Müller Sebastian S Cañeque Tatiana T Rodriguez Raphaël R Vincent-Salomon Anne A de Thé Hugues H Rossignol Rodrigue R Mechta-Grigoriou Fatima F

Cell metabolism 20180920 1

High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOCs rely on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PG ...[more]

PMID: 30244973

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Project description:RelevanceMolecular network changes are the hallmark of the pathogenesis of ovarian cancers (OCs). Network-based biomarkers benefit for the effective treatment of OC.PurposeThis study sought to identify key pathway-network alterations and network-based biomarkers for clarification of molecular mechanisms and treatment of OCs.MethodsIngenuity Pathway Analysis (IPA) platform was used to mine signaling pathway networks with 1198 human tissue mitochondrial differentially expressed proteins (mtDEPs) and compared those pathway network changes between OCs and controls. The mtDEPs in important cancer-related pathway systems were further validated with qRT-PCR and Western blot in OC cell models. Moreover, integrative analysis of mtDEPs and Cancer Genome Atlas (TCGA) data from 419 patients was used to identify hub molecules with molecular complex detection method. Hub molecule-based survival analysis and multiple multivariate regression analysis were used to identify survival-related hub molecules and hub molecule signature model.ResultsPathway network analysis revealed 25 statistically significant networks, 192 canonical pathways, and 5 significant molecular/cellular function models. A total of 52 canonical pathways were activated or inhibited in cancer pathogenesis, including antigen presentation, mitochondrial dysfunction, GP6 signaling, EIF2 signaling, and glutathione-mediated detoxification. Of them, mtDEPs (TPM1, CALR, GSTP1, LYN, AKAP12, and CPT2) in those canonical pathway and molecular/cellular models were validated in OC cell models at the mRNA and protein levels. Moreover, 102 hub molecules were identified, and they were regulated by post-translational modifications and functioned in multiple biological processes. Of them, 62 hub molecules were individually significantly related to OC survival risk. Furthermore, multivariate regression analysis of 102 hub molecules identified significant seven hub molecule signature models (HIST1H2BK, ALB, RRAS2, HIBCH, EIF3E, RPS20, and RPL23A) to assess OC survival risks.ConclusionThese findings provided the overall signaling pathway network profiling of human OCs; offered scientific data to discover pathway network-based cancer biomarkers for diagnosis, prognosis, and treatment of OCs; and clarify accurate molecular mechanisms and therapeutic targets. These findings benefit for the discovery of effective and reliable biomarkers based on pathway networks for OC predictive and personalized medicine.

Project description:Colon cancer is one of the most common cancers in the world. Multidrug resistance is one of the main reasons for failure of therapy in patients with advanced colon cancer. In previous studies, multiple methods were investigated to reverse the multidrug resistance of colon cancer cells. However, to date, no clinical method has been identified to be satisfactory. Therefore, successful reversal of drug resistance in colon cancer cells still requires new therapeutic strategies or pharmaceuticals. Wild-type p53-induced phosphatase (Wip1), a member of the 2C type serine/threonine protein phosphatase family, is closely associated with the p53 gene, which is the most important tumor-suppressor gene. Wip1 was reported to be associated with the chemosensitivity of breast cancer cells. However, the correlation between the expression of Wip1 gene and the chemosensitivity of colon cancer cells has not been reported yet. In the present study, Wip1-811 small interfering RNA (siRNA) targeting Wip1 was investigated to reverse the multidrug resistance of colon cancer cells. The siRNA duplexes were transfected into RKO colon cancer cells. The messenger RNA (mRNA) expression of Wip1 was measured by reverse transcription-quantitative polymerase chain reaction. The protein level of Wip1 was detected by western blotting. The cell viability was measured by MTS assay. The cell apoptosis and cell cycle were analyzed by flow cytometry. Intracellular adriamycin cumulative concentration was determined using flow cytometry. Wip1-811 siRNA efficiently inhibited the expression of Wip1 at the mRNA and protein levels, and enhanced the sensitivity of RKO colon cancer cells towards chemotherapy, which was accompanied by increased cell apoptosis, following the inhibition of Wip1 gene expression. These results indicate that Wip1 gene silencing could enhance the chemosensitivity of colon cancer cells, which may provide a new potential approach for the reversal of multidrug resistance in colon cancer cells.

Dataset Information

PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers.

Publications

PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers.

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