IDH2 stabilizes HIF ‐1α‐induced metabolic reprogramming and promotes chemoresistance in urothelial cancer

Abstract

Drug resistance contributes to poor therapeutic response in urothelial carcinoma (UC). Metabolomic analysis suggested metabolic reprogramming in gemcitabine‐resistant urothelial carcinoma cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promoted pyrimidine biosynthesis to increase the production of the gemcitabine competitor deoxycytidine triphosphate (dCTP) that diminishes its therapeutic effect. Furthermore, we observed that gain‐of‐function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif‐1α expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine‐resistant UC cells. Interestingly, IDH2‐mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. Since the expression of key metabolic enzymes, such as TIGAR, TKT, and CTPS1, were affected by IDH2‐mediated metabolic reprogramming and related to poor prognosis in patients, IDH2 might become a new therapeutic target for restoring chemosensitivity in chemo‐resistant urothelial carcinoma. image The role of metabolic alterations in acquired chemoresistance and molecular upstream regulators involved remain unclear. This metabolomic analysis reports isocitrate dehydrogenase 2 (IDH2) as a driver of resistance in urothelial carcinoma (UC), suggesting new avenues for targeting bladder cancer. Gemcitabine (GEM)‐resistant UC cells require aerobic glycolysis, the pentose phosphate pathway and glutamine metabolism. GEM‐resistant UC cells decrease glutamine anaplerosis through the TCA cycle, and increase the reverse α‐ketoglutarate/isocitrate reaction. By mediating the α‐ketoglutarate/isocitrate conversion, IDH2 enhances reductive glutamine metabolism, 2‐HG production and stabilization of HIF‐1α. IDH2 / HIF‐1α‐mediated metabolic reprogramming spurs molecular competition of dCTP with GEM. Depletion or pharmacological inhibition of IDH2 restores chemosensitivity.