GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis.

Autor:	Cordova RA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, United States., Misra J; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States., Amin PH; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States., Klunk AJ; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States., Damayanti NP; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, United States.; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States., Carlson KR; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States., Elmendorf AJ; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States., Kim HG; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States., Mirek ET; Department of Nutritional Sciences, Rutgers University, New Brunswick, United States., Elzey BD; Department of Comparative Pathology, Purdue University, West Lafayette, United States.; Department of Urology, Indiana University School of Medicine, Indianapolis, United States., Miller MJ; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States., Dong XC; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States., Cheng L; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, United States.; Department of Urology, Indiana University School of Medicine, Indianapolis, United States.; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, United States., Anthony TG; Department of Nutritional Sciences, Rutgers University, New Brunswick, United States., Pili R; Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, United States., Wek RC; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, United States., Staschke KA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 Sep 15; Vol. 11. Date of Electronic Publication: 2022 Sep 15.
DOI:	10.7554/eLife.81083
Abstrakt:	A stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier ( SLC ) genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels. Addition of essential amino acids or expression of 4F2 (SLC3A2) partially restored growth following loss of GCN2, suggesting that GCN2 targeting of SLC transporters is required for amino acid homeostasis needed to sustain tumor growth. A small molecule inhibitor of GCN2 showed robust in vivo efficacy in androgen-sensitive and castration-resistant mouse models of PCa, supporting its therapeutic potential for the treatment of PCa. Competing Interests: RC, JM, PA, AK, ND, KC, AE, HK, EM, BE, MM, XD, LC, RP No competing interests declared, TA is a consultant for HiberCell, Inc, RW is a member of the advisory board and holds equity in HiberCell, Inc, KS is a consultant for HiberCell, Inc and receives research support from HiberCell, Inc (© 2022, Cordova et al.)
Databáze:	MEDLINE
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