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SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors

文献类型：期刊论文

作者Wang, Xiaomin3,4; Chen, Ziqi3,4; Xu, Jun3,4; Tang, Shuai3; An, Nan3,4; Jiang, Lei1; Zhang, Yixiang1; Zhang, Shaoying5; Zhang, Qingli6; Shen, Yanyan3
刊名CELL RESEARCH
出版日期2022-04-22
页码21
ISSN号1001-0602
DOI10.1038/s41422-022-00650-w
通讯作者Huang, Min(mhuang@simm.ac.cn)
英文摘要Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1 inhibitors appear only effective in hematological tumors. The therapeutic benefit in solid tumors remains elusive, likely due to the complex tumor microenvironment. In this study, we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis, conferring a therapeutic vulnerability in IDH1-mutant solid tumors. Mechanistically, SLC1A1, a Na+-dependent glutamate transporter that is preferentially expressed in endothelial cells, facilitates the influx of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria. R-2-HG hijacks SLC1A1 to promote mitochondrial Na+/Ca2+ exchange, which activates the mitochondrial respiratory chain and fuels vascular endothelial cell migration in tumor angiogenesis. SLC1A1 deficiency in mice abolishes mIDH1-promoted tumor angiogenesis as well as the therapeutic benefit of mIDH1 inhibitor in solid tumors. Moreover, we report that HH2301, a newly discovered mIDH1 inhibitor, shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models. Together, we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular endothelial cells, and demonstrate the therapeutic potential of mIDH1 inhibitors in treating IDH1-mutant solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.
WOS关键词ONCOMETABOLITE 2-HYDROXYGLUTARATE ; MUTATIONS ; ACID ; IDH1 ; EXCHANGER ; GROWTH ; DIFFERENTIATION ; LOCALIZATION ; GLYCOLYSIS ; ASTROCYTES
资助项目National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[91957126] ; National Natural Science Foundation of China[81903640] ; National Natural Science Foundation of China[91957120] ; Program of Shanghai Academic Research Leader[20XD1424800]
WOS研究方向Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000786167800002
源URL[http://119.78.100.183/handle/2S10ELR8/299508]  
专题新药研究国家重点实验室
通讯作者Huang, Min
作者单位1.Haihe Biopharma, Shanghai, Peoples R China
2.Xiamen Univ, Sch Life Sci, Natl Inst Data Sci Hlth & Med, State Key Lab Cellular Stress Biol, Xiamen, Fujian, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.East China Normal Univ, Sch Life Sci, Inst Biomed Sci, Thanghai Key Lab Regulatory Biol, Shanghai, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Jiangsu, Peoples R China
8.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Zhejiang, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Xiaomin,Chen, Ziqi,Xu, Jun,et al. SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors[J]. CELL RESEARCH,2022:21.
APA Wang, Xiaomin.,Chen, Ziqi.,Xu, Jun.,Tang, Shuai.,An, Nan.,...&Huang, Min.(2022).SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors.CELL RESEARCH,21.
MLA Wang, Xiaomin,et al."SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors".CELL RESEARCH (2022):21.

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来源：上海药物研究所

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