GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis

• DOI: 10.1101/2022.06.17.496598
• Publication Date: 2022-06-19T05:10:22Z
• Authors: Ricardo A. Cordova; Jagannath Misra; Parth H. Amin; Angela J. Klunk; Nur P. Damayanti; Kenneth R. Carlson; Andrew J. Elmendorf; Hyeong-Geug Kim; Emily T. Mirek; Bennet D. Elzey; Marcus J. Miller; X. Charlie Dong; Liang Cheng; Tracy G. Anthony; Roberto Pili; Ronald C. Wek; Kirk A. Staschke
• Keywords: Integrated stress response

Abstract A stress adaptation pathway termed the integrated response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that eIF2 kinase GCN2 is required for sustained growth androgen-sensitive and castration-resistant models of PCa both vitro vivo, patient samples. Using RNA-seq transcriptome analysis a CRISPR-based phenotypic screen, was shown regulate expression over 60 solute-carrier ( SLC ) genes, those involved amino acid transport loss function reduces import levels. Addition essential acids or 4F2 (SLC3A2) partially restored following GCN2, suggesting targeting transporters homeostasis needed sustain tumor growth. small molecule inhibitor showed robust vivo efficacy mouse PCa, supporting its therapeutic potential treatment PCa. Significance The ISR critical maintaining levels facilitate growth, novel strategy by inducing starvation acids.