PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers (Cell metabolism, 2019, 29:156-173)

報告日期: 2019/11/01
報告時間: 17:10/18:00
報告學生: 林羽珊(英文報告)
講評老師: 林世杰
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PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers

Ge´ raldine Gentric, Yann Kieffer, Virginie Mieulet, Oumou Goundiam, Claire Bonneau, Fariba Nemati, Ilse Hurbain, Graca Raposo, Tatiana Popova, Marc-Henri Stern, Vale´rie Lallemand-Breitenbach, Sebastian M€uller, Tatiana Can˜eque, Rapha€el Rodriguez, Anne Vincent-Salomon, Hugues de The´, Rodrigue Rossignol, and Fatima Mechta-Grigoriou

Cell Metabolism. 2019, Jan; 29:156-173.

Speaker: Yu-Shan Lin                              Time: 17:10-18:00, Nov. 1, 2019

Commentator: Dr. Shih-Chieh Lin           Place: Room 602

Abstract

Metabolic reprogramming, including warburg effect, up-regulation of lipid metabolism, increase of glutaminolytic flux and mitochondrial component biogenesis, has long been recognized as the cancer hallmark [1]. Recent research have defined the tumor subgroups by their preference for aerobic glycolysis or oxidative phosphorylation (OXPHOS), while the signature of metabolic heterogeneity is still unclear in ovarian cancer. In this study, researcher classified the high-grade serous ovarian cancer (HGSOC) into two subgroups – high- and low-OXPHOS based on their expression levels of electron transport chain (ETC) by label-free proteomics and metabolomics. By measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), the authors confirmed high-OXPHOS cells tend to use mitochondrial respiration to produce ATP, while low-OXPHOS cells prefer glycolysis. In the following, the researcher revealed that there was no difference in cell proliferation, cell migration and cell growth between high- and low-OXPHOS cells, indicating better mitochondrial function didn’t contribute to tumor progression. In turn, they surprisingly found out that high-OXPHOS cells were more susceptible to chemotherapy. According to the results, the chemosensitivity in high-OXPHOS cells was caused by chronic oxidative stress, which would induce a stress-response matrix-associated domain called promyelocytic leukemia (PBL) to form nucleus bodies (NBs) and activate its downstream protein – PGC-1a. PGC-1a then bound to transcription factors and promoted ETC transcription, thus making the elevation of mitochondrial respiration in ovarian tumor. In sum, the observations in this study provide the metabolic heterogeneity in HGSOC and identify oxidative stress-dependent PML-PGC-1a pathway in defining the high-OXPHOS status.

Reference

  1. Phan LM, Yeung SC and Lee MH. (2014). Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med, 11(1):1-19.