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.
Keywords: 4F2; GCN2; ISR; amino acid transport; cancer biology; cell biology; eIF2; human; mouse; prostate cancer.
Prostate cancer is the fourth most common cancer worldwide, affecting over a million people each year. Existing drug treatments work by blocking the effects or reducing the levels of the hormone testosterone. However, these drug regimens are not always effective, so finding alternative treatments is an important area of research. One option is to target the 'integrated stress response', a pathway that acts as a genetic switch, turning on a group of genes that counteract cellular stress and are essential for the survival of cancer cells. The reason cancer cells are under stress is because they are hungry. They need to make a lot of proteins and other metabolic intermediates to grow and divide, which means they need plenty of amino acids, the building blocks that make up proteins and fuel metabolism. Amino acids enter cells through molecular gates called amino acid transporters, and scientists think the integrated stress response might play a role in this process. One of the integrated stress response components is a protein called General Control Nonderepressible 2, or GCN2 for short. In healthy cells, this protein helps to boost amino acid levels when supplies start to run low. Cordova et al. examined human prostate cancer cells to find out what role GCN2 plays in this cancer. In both lab-grown cells and tissue from patients, GCN2 was active and played a critical role in prostate tumor growth by turning on the genes for amino acid transporters to increase the levels of amino acids entering the cancer cells. Deleting the gene for GCN2, or blocking its effects with an experimental drug, slowed the growth of cultured prostate cancer cells and reduced tumor growth in mice. In these early experiments, Cordova et al. did not notice any toxic side effects to healthy tissues. If GCN2 works in the same way in humans as it does in mice, blocking it might help to control prostate cancer growth. The integrated stress response is also active in other cancer types, so the same logic might apply to different tumors. However, before GCN2 blockers can become treatments, researchers need a more complete understanding of their molecular effects.
© 2022, Cordova et al.