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首页> 外文期刊>Cell metabolism >PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers
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PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers

机译：PML调节的线粒体代谢增强人卵巢癌中的化学敏感性

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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-1 alpha 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 alpha. Active PGC-1 alpha increases synthesis of electron transport chain complexes, thereby promoting mito-chondrial 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 alpha-dependent mechanism that promotes OXPHOS metabolism and chemo-sensitivity in ovarian cancer.
机译：高级浆液卵巢癌（HGSOC）仍然是未满足的医疗挑战。在这里，我们在Hgsoc中解开了一种意外的代谢异质性。通过组合蛋白质组学，代谢组和生物流学分析，我们鉴定两种分子亚组，低和高氧基。虽然低毒物表现出糖酵解代谢，但高汤酚Hgsocs依赖于氧化磷酸化，得到谷氨酰胺和脂肪酸氧化，并显示慢性氧化应激。我们在高汤酚HGSOC的代谢特征中确定了PML-PGC-1α轴的重要作用。在高汤酚肿瘤中，慢性氧化应激促进PML-核体的聚集，导致转录共激活剂PGC-1α的激活。活性PGC-1α增加了电子传输链复合物的合成，从而促进了弥伸性呼吸的术。重要的是，高汤酚HGSOCs表现出对常规化疗的响应增加，其中氧化应激，PML和潜在的硬质子发挥关键功能。集体，我们的数据建立了应激介导的PML-PGC-1α依赖性机制，促进卵巢癌中的奥帕洛斯代谢和化学敏感性。

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  • 来源
    《Cell metabolism》 |2019年第1期|共28页
  • 作者

    Gentric Geraldine; Kieffer Yann; Mieulet Virginie; Goundiam Oumou; Bonneau Claire; Nemati Fariba; Hurbain Ilse; Raposo Graca; Popova Tatiana; Stern Marc-Henri; Lallemand-Breitenbach Valerie; Muller Sebastian; Caneque Tatiana; Rodriguez Raphael; Vincent-Salomon Anne; de The Hugues; Rossignol Rodrigue; Mechta-Grigoriou Fatima;

  • 作者单位

    PSL Res Univ Stress &

    Canc Lab Equipe Labelisee Ligue Natl Canc Inst Curie 26 Rue Ulm F-75005;

    PSL Res Univ Stress &

    Canc Lab Equipe Labelisee Ligue Natl Canc Inst Curie 26 Rue Ulm F-75005;

    PSL Res Univ Stress &

    Canc Lab Equipe Labelisee Ligue Natl Canc Inst Curie 26 Rue Ulm F-75005;

    PSL Res Univ Stress &

    Canc Lab Equipe Labelisee Ligue Natl Canc Inst Curie 26 Rue Ulm F-75005;

    PSL Res Univ Stress &

    Canc Lab Equipe Labelisee Ligue Natl Canc Inst Curie 26 Rue Ulm F-75005;

    Inst Curie Lab Preclin Invest Translat Res Dept 26 Rue Ulm F-75248 Paris France;

    PSL Res Univ Inst Curie CNRS UMR 144 F-75005 Paris France;

    PSL Res Univ Inst Curie CNRS UMR 144 F-75005 Paris France;

    INSERM U830 26 Rue Ulm F-75005 Paris France;

    INSERM U830 26 Rue Ulm F-75005 Paris France;

    PSL Res Univ Coll France Pl Marcellin Berthelot F-75005 Paris France;

    PSL Res Univ Chem Biol Canc Equipe Labellisee Ligue Natl Canc CNRS UMR3666 Inserm U1143 Inst;

    PSL Res Univ Chem Biol Canc Equipe Labellisee Ligue Natl Canc CNRS UMR3666 Inserm U1143 Inst;

    PSL Res Univ Chem Biol Canc Equipe Labellisee Ligue Natl Canc CNRS UMR3666 Inserm U1143 Inst;

    Inst Curie Hosp Dept Pathol 26 Rue Ulm F-75248 Paris France;

    PSL Res Univ Coll France Pl Marcellin Berthelot F-75005 Paris France;

    Univ Bordeaux INSERM U1211 146 Rue Leo Saignat F-33000 Bordeaux France;

    PSL Res Univ Stress &

    Canc Lab Equipe Labelisee Ligue Natl Canc Inst Curie 26 Rue Ulm F-75005;

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  • 正文语种 eng
  • 中图分类 内分泌腺疾病及代谢病;
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