Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction

作者：Chun-Ting Cheng, Yue Qi, Yi-Chang Wang, K. Kevin, Yiyin Chung, Ching Ouyang, Yun‐Ru Chen, Myung Eun Oh, Xiangpeng Sheng, Yulong Tang, Yun-Ru Liu, H. Helen Lin, Ching‐Ying Kuo, Dustin E. Schones, Christina M. Vidal, Jenny C.-Y. Chu, Hung-Jung Wang, Yu-Han Chen, Kyle M. Miller, Peiguo Chu, Yun Yen, Lei Jiang, Hsing-Jien Kung, David K. Ann · 发表于：Communications Biology · 年份：2018 · DOI：10.1038/s42003-018-0178-4 · 被引用次数：186 · 研究领域：Cancer Research and Treatments、Cancer, Hypoxia, and Metabolism、Amino Acid Enzymes and Metabolism

(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.