PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers

Cell Metab. 2019 Jan 8;29(1):156-173.e10. doi: 10.1016/j.cmet.2018.09.002. Epub 2018 Sep 20.


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.

Keywords: OXPHOS; PGC-1α; chemoresistance; ferroptosis; ovarian cancer; oxidative stress; peroxisome proliferator-activated receptor gamma coactivator-1α; promyelocytic leukemia protein; reactive oxygen species; response to treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma / metabolism*
  • Cell Line, Tumor
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Mitochondria / metabolism*
  • Ovarian Neoplasms / metabolism*
  • Oxidative Phosphorylation
  • Oxidative Stress
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / physiology*
  • Promyelocytic Leukemia Protein / physiology*


  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Promyelocytic Leukemia Protein
  • PML protein, human