摘要
Autophagy is the principal catabolic response to nutrient starvation and is necessary to clear dysfunctional or damaged organelles, but excessive autophagy can be cytotoxic or cytostatic and contributes to cell death. Depending on the abundance of enzymes involved in molecule biosynthesis, cells can be dependent on uptake of exogenous nutrients to provide these molecules. Argininosuccinate synthetase 1 (ASS1) is a key enzyme in arginine biosynthesis, and its abundance is reduced in many solid tumors,making them sensitive to external arginine depletion. We demonstrated that prolonged arginine starvation by exposure to ADI-PEG20 (pegylated arginine deiminase) induced autophagy-dependent death of ASS1-deficient breast cancer cells, because these cells are arginine auxotrophs (dependent on uptake of extracellular arginine). Indeed, these breast cancer cells died in culture when exposed to ADI-PEG20 or cultured in the absence of arginine. Arginine starvation induced mitochondrial oxidative stress, which impaired mitochondrial bioenergetics and integrity. Furthermore, arginine starvation killed breast cancer cells in vivo and in vitro only if they were autophagy-competent. Thus, a key mechanism underlying the lethality induced by prolonged arginine starvationwas the cytotoxic autophagy that occurred in response tomitochondrial damage. Last, ASS1 was either low in abundance or absent in more than 60% of 149 random breast cancer biosamples, suggesting that patients with such tumors could be candidates for arginine starvation therapy.
原文 | 英語 |
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頁(從 - 到) | ra31 |
期刊 | Science Signaling |
卷 | 7 |
發行號 | 319 |
DOIs | |
出版狀態 | 已發佈 - 4月 1 2014 |
ASJC Scopus subject areas
- 生物化學
- 分子生物學
- 細胞生物學
指紋
深入研究「Cancer: Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells」主題。共同形成了獨特的指紋。資料集
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Characterization of Gene Expression in ASS1-Deficient Breast Cancer Cells
Qiu, F. (Contributor), Liu, X. (Contributor), Xu, J. (Contributor), Gaur, S. (Contributor), Zhang, H. (Contributor), Zheng, S. (Contributor), Yen, Y. (Contributor) & Huang, J. (Contributor), ArrayExpress, 2014
https://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-53838
資料集: Dataset