國家衛生研究院 NHRI:Item 3990099045/11565
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    题名: Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction
    作者: Cheng, CT;Qi, Y;Wang, YC;Chi, KK;Chung, Y;Ouyang, C;Chen, YR;Oh, ME;Sheng, X;Tang, Y;Liu, YR;Lin, HH;Kuo, CY;Schones, D;Vidal, CM;Chu, JC;Wang, HJ;Chen, YH;Miller, KM;Chu, P;Yen, Y;Jiang, L;Kung, HJ;Ann, DK
    贡献者: Institute of Biotechnology and Pharmaceutical Research;Institute of Molecular and Genomic Medicine
    摘要: Defective arginine synthesis, due to the silencing of argininosuccinate synthase 1 (ASS1), is a common metabolic vulnerability in cancer, known as arginine auxotrophy. Understanding how arginine depletion kills arginine-auxotrophic cancer cells will facilitate the development of anti-cancer therapeutic strategies. Here we show that depletion of extracellular arginine in arginine-auxotrophic cancer cells causes mitochondrial distress and transcriptional reprogramming. Mechanistically, arginine starvation induces asparagine synthetase (ASNS), depleting these cancer cells of aspartate, and disrupting their malate-aspartate shuttle. Supplementation of aspartate, depletion of mitochondria, and knockdown of ASNS all protect the arginine-starved cells, establishing the causal effects of aspartate depletion and mitochondrial dysfunction on the arginine starvation-induced cell death. Furthermore, dietary arginine restriction reduced tumor growth in a xenograft model of ASS1-deficient breast cancer. Our data challenge the view that ASNS promotes homeostasis, arguing instead that ASNS-induced aspartate depletion promotes cytotoxicity, which can be exploited for anti-cancer therapies.
    日期: 2018-10-26
    關聯: Communications Biology. 2018 Oct 26;1:Article number 178.
    Link to: http://dx.doi.org/10.1038/s42003-018-0178-4
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2399-3642&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000461126500178
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85063369979
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