Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism

Cisplatin is currently one of the most effective chemotherapeutic drugs used for treating ovarian cancer; however, resistance to cisplatin is common. In this study, we explored an experimental strategy for overcoming cisplatin resistance of human ovarian cancer from the new perspective of cancer cell metabolism. By using two pairs of genetically matched cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable alpha subunit of HIF-1, HIF-1 alpha, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1 alpha degradation but did not downregulate HIF-1 alpha in their cisplatin-resistant counterparts. Overexpression of a degradation resistant HIF-1 alpha (HIF-1 alpha Delta ODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1 alpha or pharmacological promotion of HIF-1 alpha degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. We further demonstrated that knockdown of HIF-1 alpha improved the response of cisplatin-resistant ovarian cancer cells to cisplatin by redirecting the aerobic glycolysis in the resistant cancer cells toward mitochondrial oxidative phosphorylation, leading to cell death through overproduction of reactive oxygen species. Our findings suggest that the HIF-1 alpha-regulated cancer metabolism pathway could be a novel target for overcoming cisplatin resistance in ovarian cancer. (C) 2016 Elsevier Ireland Ltd. All rights reserved.