ATM inhibition drives metabolic adaptation via induction of macropinocytosis
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 18, 2022
- Source ID
- 10.1083/jcb.202007026
Entities
People
- Aidan R. Cole
- Chi-Wei Chen
- Eliana von Krusenstiern
- Erika L. Varner
- Erika S Dahl
- Katherine M Aird
- Kelly E Leon
- Nathaniel W. Snyder
- Naveen Kumar Tangudu
- Raquel Buj
- Richard S. Fang
- Zhentai Huang
Organizations
- Congressionally Directed Medical Research Programs
- National Institutes of Health
- Temple University
- University of Pittsburgh School of Medicine