PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Cell Metabolism Year : 2019

PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers

Fariba Némati
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  • PersonId : 955397

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-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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Dates and versions

inserm-02437801 , version 1 (13-01-2020)

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Géraldine Gentric, Yann Kieffer, Virginie Mieulet, Oumou Goundiam, Claire Bonneau, et al.. PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers. Cell Metabolism, 2019, 29 (1), pp.156-173.e10. ⟨10.1016/j.cmet.2018.09.002⟩. ⟨inserm-02437801⟩
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