PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers
In: ISSN: 1550-4131 ; Cell Metabolism ; https://inserm.hal.science/inserm-02437801 ; Cell Metabolism, 2019, 29 (1), pp.156-173.e10. ⟨10.1016/j.cmet.2018.09.002⟩, 2019
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Zugriff:
International audience ; 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-1α 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-1α. Active PGC-1α 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-1α-dependent mechanism that promotes OXPHOS metabolism and chemosensitivity in ovarian cancer.
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PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers
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Autor/in / Beteiligte Person: | Gentric, Géraldine ; Kieffer, Yann ; Mieulet, Virginie ; Goundiam, Oumou ; Bonneau, Claire ; Némati, Fariba ; Hurbain, Ilse ; Raposo, Graça ; Popova, Tatiana ; Stern, Marc-Henri ; Lallemand-Breitenbach, Valérie ; Müller, Sebastian ; Cañeque, Tatiana ; Rodriguez, Raphaël ; Vincent-Salomon, Anne ; de Thé, Hugues ; Rossignol, Rodrigue ; Mechta-Grigoriou, Fatima ; Unité de génétique et biologie des cancers (U830) ; Université Paris Descartes - Paris 5 (UPD5)-Institut Curie Paris -Institut National de la Santé et de la Recherche Médicale (INSERM) ; Département de Recherche Translationnelle ; Institut Curie Paris ; Compartimentation et dynamique cellulaires (CDC) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie Paris -Centre National de la Recherche Scientifique (CNRS) ; BioImaging Cell and Tissue Core Facility (PICT-IBiSA) ; Pathologie et virologie moléculaire (PVM (UMR_7151)) ; Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143) ; Université Paris Descartes - Paris 5 (UPD5)-Institut Curie Paris -Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS) ; Département de Pathologie Curie ; Collège de France - Chaire Oncologie cellulaire et moléculaire ; Génomes, biologie cellulaire et thérapeutiques (GenCellDis (U944 / UMR7212)) ; Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) ; Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM) ; Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM) ; G.G. was supported by funding from the Foundation ARC. Y.K. was supported by the Foundation for Medical Research (FRM) and the SiRIC-Curie program (INCa-DGOS-4654). F.M.-G., C.B., and V.M. were supported by the Institut National de la Sante´ et de la Recherche Me´ dicale (Inserm). O.G. was funded by Institut Curie. R. Rodriguez is supported by ERC (grant number 647973). The experimental work was supported by grants from the Ligue Nationale Contre le Cancer (Labelisation), Institut Curie, Inserm (PC201317), INCa (2011-1-PLBIO-12-IC-1 and 2015-1-RT-04-ICR-1), and the Simone and Cino del Duca Foundation for the Grand Prix attributed to F.M.-G. F.M.-G is very grateful to her funders for providing support these last years. ; European Project: 647973,H2020,ERC-2014-CoG,Drug-Seq(2015) |
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Zeitschrift: | ISSN: 1550-4131 ; Cell Metabolism ; https://inserm.hal.science/inserm-02437801 ; Cell Metabolism, 2019, 29 (1), pp.156-173.e10. ⟨10.1016/j.cmet.2018.09.002⟩, 2019 |
Veröffentlichung: | HAL CCSD ; Elsevier, 2019 |
Medientyp: | academicJournal |
DOI: | 10.1016/j.cmet.2018.09.002 |
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