Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction

Chun Ting Cheng, Yue Qi, Yi Chang Wang, Kevin K. Chi, Yiyin Chung, Ching Ouyang, Yun Ru Chen, Myung Eun Oh, Xiangpeng Sheng, Yulong Tang, Yun Ru Liu, H. Helen Lin, Ching Ying Kuo, Dustin Schones, Christina M. Vidal, Jenny C.Y. Chu, Hung Jung Wang, Yu Han Chen, Kyle M. Miller, Peiguo ChuYun Yen, Lei Jiang, Hsing-Jien Kung, David K. Ann

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Article number178
JournalCommunications Biology
Volume1
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

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    Cheng, C. T., Qi, Y., Wang, Y. C., Chi, K. K., Chung, Y., Ouyang, C., Chen, Y. R., Oh, M. E., Sheng, X., Tang, Y., Liu, Y. R., Lin, H. H., Kuo, C. Y., Schones, D., Vidal, C. M., Chu, J. C. Y., Wang, H. J., Chen, Y. H., Miller, K. M., ... Ann, D. K. (2018). Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction. Communications Biology, 1(1), [178]. https://doi.org/10.1038/s42003-018-0178-4