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http://ir.nhri.org.tw/handle/3990099045/11565
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| Title: | Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction |
| Authors: | 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 |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research;Institute of Molecular and Genomic Medicine |
| Abstract: | 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. |
| Date: | 2018-10-26 |
| Relation: | 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 |
| Appears in Collections: | [王鴻俊] 期刊論文
[其他] 期刊論文
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| PUB30393775.pdf | | 1817Kb | Adobe PDF | 298 | View/Open |
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