Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction
Journal
Communications Biology
Journal Volume
1
Journal Issue
1
Pages
178
Date Issued
2018
Author(s)
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.
Schones D.
Vidal C.M.
Chu J.C.-Y.
Wang H.-J.
Chen Y.-H.
Miller K.M.
Chu P.
Yen Y.
Jiang L.
Kung H.-J.
Ann D.K.
Abstract
(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.
SDGs
Type
journal article