GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis

被引：33

作者：

Cordova, Ricardo A. ^{[1
,2
]}

Misra, Jagannath ^{[1
]}

Amin, Parth H. ^{[1
]}

Klunk, Anglea J. ^{[1
]}

Damayanti, Nur P. ^{[2
,3
]}

Carlson, Kenneth R. ^{[1
]}

Elmendorf, Andrew J. ^{[1
]}

Kim, Hyeong-Geug ^{[1
]}

Mirek, Emily T. ^{[4
]}

Elzey, Bennet D. ^{[5
,6
]}

Miller, Marcus J. ^{[7
]}

Dong, X. Charlie ^{[1
]}

Cheng, Liang ^{[2
,6
,8
,10
]}

Anthony, Tracy G. ^{[4
]}

Pili, Robero ^{[9
]}

Wek, Ronald C. ^{[1
,2
]}

Staschke, Kirk A. ^{[1
,2
]}

机构：

[1] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[2] Indiana Univ, Melvin & Bren Simon Comprehens Canc Ctr, Indianapolis, IN 46204 USA

[3] Indiana Univ Sch Med, Dept Neurol Surg, Indianapolis, IN 46202 USA

[4] Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ USA

[5] Purdue Univ, Dept Comparat Pathol, W Lafayette, IN 47907 USA

[6] Indiana Univ Sch Med, Dept Urol, Indianapolis, IN 46202 USA

[7] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[8] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA

[9] Univ Buffalo, Jacobs Sch Med & Biomed Sci, Buffalo, NY 14260 USA

[10] Brown Univ, Warren Alpert Med Sch, Dept Pathol & Lab Med, Providence, RI 02912 USA

来源：

ELIFE | 2022年 / 11卷

关键词：

ISR; GCN2; eIF2; amino acid transport; prostate cancer; 4F2; Human; Mouse; UNFOLDED PROTEIN RESPONSE; RECEPTOR SPLICE VARIANTS; ANDROGEN RECEPTOR; TRANSFER-RNA; TRANSLATIONAL CONTROL; CASTRATION-RESISTANT; EIF2-ALPHA KINASE; STRESS RESPONSES; OXIDATIVE STRESS; CELL LINE;

D O I：

10.7554/eLife.81083

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：31

共 86 条

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