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ATM inhibition drives metabolic adaptation via induction of macropinocytosis
Huang, Zhentai Chen, Chi-Wei Buj, Raquel Tangudu, Naveen Kumar Fang, Richard S. Leon, Kelly E. Dahl, Erika S. Varner, Erika L. von Krusenstiern, Eliana Cole, Aidan R.
Huang, Zhentai
Chen, Chi-Wei
Buj, Raquel
Tangudu, Naveen Kumar
Fang, Richard S.
Leon, Kelly E.
Dahl, Erika S.
Varner, Erika L.
von Krusenstiern, Eliana
Cole, Aidan R.
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Journal article
Date
2022-11-18
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Cardiovascular Sciences
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http://dx.doi.org/10.1083/jcb.202007026
Abstract
Macropinocytosis is a nonspecific endocytic process that may enhance cancer cell survival under nutrient-poor conditions. Ataxia-Telangiectasia mutated (ATM) is a tumor suppressor that has been previously shown to play a role in cellular metabolic reprogramming. We report that the suppression of ATM increases macropinocytosis to promote cancer cell survival in nutrient-poor conditions. Combined inhibition of ATM and macropinocytosis suppressed proliferation and induced cell death both in vitro and in vivo. Supplementation of ATM-inhibited cells with amino acids, branched-chain amino acids (BCAAs) in particular, abrogated macropinocytosis. Analysis of ATM-inhibited cells in vitro demonstrated increased BCAA uptake, and metabolomics of ascites and interstitial fluid from tumors indicated decreased BCAAs in the microenvironment of ATM-inhibited tumors. These data reveal a novel basis of ATM-mediated tumor suppression whereby loss of ATM stimulates protumorigenic uptake of nutrients in part via macropinocytosis to promote cancer cell survival and reveal a potential metabolic vulnerability of ATM-inhibited cells.
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Zhentai Huang, Chi-Wei Chen, Raquel Buj, Naveen Kumar Tangudu, Richard S. Fang, Kelly E. Leon, Erika S. Dahl, Erika L. Varner, Eliana von Krusenstiern, Aidan R. Cole, Nathaniel W. Snyder, Katherine M. Aird; ATM inhibition drives metabolic adaptation via induction of macropinocytosis. J Cell Biol 2 January 2023; 222 (1): e202007026. doi: https://doi.org/10.1083/jcb.202007026
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Rockefeller University Press
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Journal of Cell Biology (JCB), Vol. 222, No. 1
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