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IDH2 稳定 HIF-1α 诱导的代谢重编程，并促进膀胱癌的化疗耐药性。

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

机构信息

Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Department of Urology, Tokai University School of Medicine, Tokyo, Japan.

出版信息

EMBO J. 2023 Feb 15;42(4):e110620. doi: 10.15252/embj.2022110620. Epub 2023 Jan 13.

DOI:10.15252/embj.2022110620
PMID:36637036
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9929641/
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-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.

摘要

耐药性导致尿路上皮癌（UC）治疗反应不佳。代谢组学分析表明，吉西他滨耐药性尿路上皮癌细胞发生代谢重编程，有氧糖酵解和戊糖磷酸途径（PPP）的代谢刺激增加嘧啶生物合成，增加吉西他滨竞争物脱氧胞苷三磷酸（dCTP）的产生，从而降低其治疗效果。此外，我们观察到，异柠檬酸脱氢酶 2（IDH2）的功能获得诱导还原性谷氨酰胺代谢，以稳定 Hif-1α的表达，从而刺激吉西他滨耐药性 UC 细胞中的有氧糖酵解和 PPP 旁路。有趣的是，IDH2 介导的代谢重编程还通过增加 NADPH 和谷胱甘肽的产生来引起交叉耐药性顺铂（CDDP），从而提高抗氧化防御能力。下调或药理学抑制 IDH2 可恢复化疗敏感性。由于关键代谢酶的表达，如 TIGAR、TKT 和 CTPS1，受到 IDH2 介导的代谢重编程的影响，并与患者的预后不良相关，因此 IDH2 可能成为恢复化疗耐药性尿路上皮癌化疗敏感性的新治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c41/9929641/8f92fe63e79f/EMBJ-42-e110620-g014.jpg
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