PGC1α regulates mitochondrial oxidative phosphorylation involved in cisplatin resistance in ovarian cancer cells via nucleo-mitochondrial transcriptional feedback

• Published in: Experimental cell research 2021-01, Vol.398 (1), p.112369, Article 112369
• Main Authors: Shen, Luyan, Zhou, Li, Xia, Meihui, Lin, Nan, Ma, Jiaoyan, Dong, Delu, Sun, Liankun
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; Antineoplastic Agents - pharmacology; APOPTOSIS; Apoptosis - drug effects; Apoptosis - genetics; CELL NUCLEI; Cell Nucleus - drug effects; Cell Nucleus - genetics; Cell Nucleus - metabolism; CHEMOTHERAPY; Cisplatin - pharmacology; Cisplatin resistance; DNA; Drug Resistance, Neoplasm - drug effects; DRUGS; Female; Humans; LACTIC ACID; METABOLISM; MITOCHONDRIA; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; MOLECULES; mtDNA transcription; NEOPLASMS; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; OVARIES; OXIDATION; Oxidative Phosphorylation - drug effects; OXPHOS; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; PHOSPHORYLATION; TOXICITY; TRANSCRIPTION; TRANSCRIPTION FACTORS; Transcription, Genetic - drug effects; Tumor Cells, Cultured
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2020.112369

Mitochondria play an important role in effective cell energy production and cell survival under stress conditions, such as treatment with chemotherapeutic drugs. Mitochondrial biogenesis is increased in ovarian cancer tissues, which is accompanied by alteration of mitochondrial energy metabolism, structure, and dynamics. These factors are involved in tumorigenesis and apoptosis resistance, highlighting the role of mitochondria in resisting cisplatin toxicity. Cisplatin-resistant ovarian cancer cells are dependent on mitochondrial OXPHOS for energy supply, and intracellular PGC1α-mediated mitochondrial biogenesis levels are increased in this cell line, indicating the important role of mitochondrial oxidative phosphorylation in cisplatin resistance. As PGC1α is a key molecule for integrating and coordinating nuclear DNA and mitochondrial DNA transcriptional machinery, an investigation into the regulatory mechanism PGC1α in mitochondrial energy metabolism via transcription may provide new clues for solving chemotherapy resistance. In the present study, it was demonstrated that inhibiting the expression of PGC1α decreased nuclear and mitochondrial DNA transcription factor expression, leading to increased lactic acid production and decreased cellular oxygen consumption and mitochondrial oxidative phosphorylation. Furthermore, mitochondrial stress-induced ROS production, as a feedback signal from mitochondria to the cell nucleus, increased PGC1α expression in SKOV3/DDP cells, which was involved in mitochondrial oxidative phosphorylation regulation. Collectively, the present study provides evidence that PGC1α-mediated nuclear and mitochondrial transcription feedback regulates energy metabolism and is involved in ovarian cancer cells escaping apoptosis during cisplatin treatment.