氧化磷酸化
氧化应激
癌症研究
糖酵解
生物
谷氨酰胺
线粒体
新陈代谢
细胞生物学
生物化学
氨基酸
作者
Géraldine Gentric,Yann Kieffer,Virginie Mieulet,Oumou Goundiam,Claire Bonneau,Fariba Némati,Ilse Hurbain,Graça Raposo,Tatiana Popova,Marc‐Henri Stern,Valérie Lallemand-Breitenbach,Sebastian Mûller,Tatiana Cañeque,Raphaël Rodriguez,Anne Vincent‐Salomon,Rodrigue Rossignol,Fatima Mechta‐Grigoriou
出处
期刊:Cell Metabolism
[Elsevier]
日期:2019-01-01
卷期号:29 (1): 156-173.e10
被引量:157
标识
DOI:10.1016/j.cmet.2018.09.002
摘要
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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