Mitochondrial superoxide sustains a senescence-like phenotype in PARP- inhibited ovarian cancer cells by stabilizing HIF1α

Ovarian cancer is the deadliest gynecological malignant tumor and is known as the “silent killer”. PARP inhibitors are being increasingly used for their excellent efficacy in the treatment of ovarian cancer. While PARP inhibitors are known to interfere with DNA repair and cause DNA damage, the fates of cancer cells and associated metabolic features in response to PARP inhibition are not well characterized. We herein show that ovarian cancer cells treated with PARP inhibitors exhibit a senescence-like phenotype that is characterized by cell cycle arrest, positive staining of senescence-associated β-gal, and increased accumulation of dysfunctional mitochondria. The survival of senescence-like cells is sustained by glycolysis that is driven by an augmented axis of mitochondrial reactive oxygen species (mtROS) and HIF1α. Mitochondrial antioxidant, inhibition of HIF1α activation and restriction of glycolysis can each block the entry into and the sustenance of the senescence-like state in PARP-inhibited ovarian cancer cells. The senescence-like phenotype, HIF1α activation and lactate production were attenuated in tumor xenografts co-treated with PARP inhibitor Rucaparib and mitochondrial antioxidant. The metabolic reliance on mtROS-driven glycolysis in ovarian cancer cells treated with PARP inhibitors has implications in cancer treatment. • PARP inhibition induces a senescence-like phenotype in ovarian cancer cells. • PARP inhibition causes mitochondrial dysfunction and mtROS buildup. • Survival of senescence-like cells relies on glycolysis driven by mtROS-HIF1α axis. • Mitochondrial antioxidant destabilizes HIF1α and abrogates senescence-like phenotype in vivo.