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

Keisuke Shigeta, Masanori Hasegawa, Takako Hishiki, Yoshiko Naito, Yuto Baba, Shuji Mikami, Kazuhiro Matsumoto, Ryuichi Mizuno, Akira Miyajima, Eiji Kikuchi, Hideyuki Saya, Takeo Kosaka, Mototsugu Oya

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere110620
JournalEMBO Journal
Issue number4
Publication statusPublished - 2023 Feb 15
Externally publishedYes


  • chemoresistance
  • hypoxia-inducible factor-1α
  • isocitrate dehydrogenase 2
  • metabolomic reprogramming
  • urothelial carcinoma

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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