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-1a 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.

Glutamine metabolism prognostic index predicts tumour microenvironment characteristics and therapeutic efficacy in ovarian cancer

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The association between serum hypoxia inducible factor-1α level and urothelial bladder cancer: A preliminary study

“…Hypoxic condition upregulates several proteins including HIF-1α that it is important for adaptation of tumor, including UBC, in hypoxic condition. Angiogenesis or neovascularization is the end point of this adaptation (3,4,6), Hypoxia is also the culprit of treatment resistance in many cancers (8,10) and HIF-1α is one of the underlying etiologies (11)(12)(13). Binding of HIF-1α with its receptor in the nucleus promotes cell proliferation, migration, and invasion.…”

m6A Demethylase FTO Stabilizes LINK-A to Exert Oncogenic Roles via MCM3-Mediated Cell Cycle Progression and HIF-1α Activation

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