生物
尿路上皮癌
癌症研究
重编程
细胞生物学
生物化学
膀胱癌
癌症
遗传学
基因
作者
Keisuke Shigeta,Masanori Hasegawa,Takako Hishiki,Yoshiko Naito,Yoshihiko Baba,Shuji Mikami,Kazuhiro Matsumoto,Ryuichi Mizuno,Akira Miyajima,Eiji Kikuchi,Hideyuki Saya,Eiji Kikuchi,Mototsugu Oya
标识
DOI:10.15252/embj.2022110620
摘要
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.
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