Wild Type IDH2-dependent stabilization of HIF1-a Induces Metabolic Reprogramming for Acquiring Chemo-resistance in Urothelial Carcinoma

The poor therapeutic response to cancer therapy due to drug resistance remains an unresolved problem for advanced urothelial carcinoma (UC). Metabolome analysis suggested metabolic reprogramming in gemcitabine-resistant UC cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promote pyrimidine biosynthesis to increase the production of deoxycytidine triphosphate (dCTP), which competes with gemcitabine to diminish its therapeutic effect.Furthermore, we observed that isocitrate dehydrogenase 2 (IDH2) gain of function induced the reductive glutamine metabolism, a so-called reductive tricarboxylic acid (TCA) cycle, to further stabilize Hif1-a expression and was suspected as master regulator for stimulating aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also comprised cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione (GSH) production. The downregulation or pharmacological suppression of IDH2 restored chemosensitivity. Since the expressions of key metabolic enzymes, such as TIGAR, TKT, and CTPS1, are affected by IDH2 mediated metabolic reprogramming and related to a poor prognosis, IDH2 could become a new therapeutic target for restoring chemosensitivity in chemo-resistant UC.