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

研究成果: Article査読

13 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号e110620
ジャーナルEMBO Journal
42
4
DOI
出版ステータスPublished - 2023 2月 15

ASJC Scopus subject areas

  • 神経科学一般
  • 分子生物学
  • 生化学、遺伝学、分子生物学一般
  • 免疫学および微生物学一般

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