Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction. (December 2018)

• Record Type: Journal Article
• Authors: Cheng, Chun-Ting; Qi, Yue; Wang, Yi-Chang; Chi, Kevin; Chung, Yiyin; Ouyang, Ching; Chen, Yun-Ru; Oh, Myung; Sheng, Xiangpeng; Tang, Yulong; Liu, Yun-Ru; Lin, H.; Kuo, Ching-Ying; Schones, Dustin; Vidal, Christina; Chu, Jenny; Wang, Hung-Jung; Chen, Yu-Han; Miller, Kyle; Chu, Peiguo; Yen, Yun; Jiang, Lei; Kung, Hsing-Jien; Ann, David
• Is Part Of: Communications biology. Volume 1:Number 1(2018)
• Page Start: 1
• Page End: 15
• Publication Date: 2018-12
• Subjects: Systems biology -- Periodicals; 570.113
• DOI: 10.1038/s42003-018-0178-4
• Languages: English
• ISSNs: 2399-3642

Abstract

Abstract Defective arginine synthesis, due to the silencing ofargininosuccinate 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. Chun-Ting Cheng et al. demonstrate that arginine starvation kills arginine-auxotrophic cancer cells by depleting them of aspartate through asparagine synthetase (ASNS) and disrupting their mitochondrial metabolism. This study presents ASNS-induced aspartate depletion as an anti-cancer therapeutic strategy.