ABT737 reverses cisplatin resistance by targeting glucose metabolism of human ovarian cancer cells

The poor prognosis and high mortality of patients with ovarian cancer result in part from their poor response to platinum-based chemotherapy. However, the precise mechanism behind cisplatin resistance is still not fully understood. In the present study, the authors explored the mechanism of resistance to cisplatin from the perspective of glucose metabolism in human ovarian cancer. The experiments using genetically matched ovarian cancer cell lines SKOV3 (cisplatin-sensitive) and SKOV3/DDP (cisplatin-resistant) in the present study provided some important findings. First, in comparison to SKOV3 cells, SKOV3/DDP cells exhibited decreased dependence on aerobic glycolysis and an increased demand for glucose. Secondly, the stable overexpression of Bcl-2 and ability to shift metabolism towards oxidative phosphorylation (OXPHOS) in SKOV3/DDP cells were associated with increased oxygen consumption. Furthermore, the metabolic characteristic of elevated OXPHOS primarily comprised most mitochondrial-derived reactive oxygen species (ROS) and, at least in part, contributed to the slight pro-oxidant state of SKOV3/DDP cells in turn. Thirdly, SKOV3/DDP cells reset the redox balance by overexpressing the key enzyme glucose 6-phosphate dehydrogenase (G6PD) of the pentose phosphate pathway to eliminate the cytotoxicity of highly elevated ROS. Furthermore, the inhibition of Bcl-2 reduced the OXPHOS and sensitivity of SKOV3/DDP cells to cisplatin in a selective manner. Furthermore, when combined with 2-deoxyglucose (2-DG), the anticancer effect of the Bcl-2 inhibitor ABT737 was greatly potentiated and hypoxia-inducible factor 1α (HIF-1α) appeared to be closely associated with Bcl-2 family members in the regulation of glucose metabolism. These results suggested that the special glucose metabolism in SKOV3/DDP cells might be selectively targeted by disrupting Bcl-2-dependent OXPHOS.