ATM inhibition drives metabolic adaptation via induction of macropinocytosis.

Autor:	Huang Z; Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Chen CW; Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Buj R; Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Tangudu NK; Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Fang RS; Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Leon KE; Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.; Biomedical Sciences Graduate Program, Penn State College of Medicine, Hershey, PA., Dahl ES; Biomedical Sciences Graduate Program, Penn State College of Medicine, Hershey, PA., Varner EL; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University, Philadelphia, PA., von Krusenstiern E; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University, Philadelphia, PA., Cole AR; Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Snyder NW; Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Temple University, Philadelphia, PA., Aird KM; Department of Pharmacology & Chemical Biology and UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2023 Jan 02; Vol. 222 (1). Date of Electronic Publication: 2022 Nov 18.
DOI:	10.1083/jcb.202007026
Abstrakt:	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. (© 2022 Huang et al.)
Databáze:	MEDLINE
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