Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer.

Cancers invoke various pathways to mitigate external and internal stresses to continue their growth and progression. We previously reported that the eIF2 kinase GCN2 and the integrated stress response are constitutively active in prostate cancer (PCa) and are required to maintain amino acid homeostasis needed to fuel tumor growth. However, although loss of GCN2 function reduces intracellular amino acid availability and PCa growth, there is no appreciable cell death. Here, we discovered that the loss of GCN2 in PCa induces prosenescent p53 signaling. This p53 activation occurred through GCN2 inhibition–dependent reductions in purine nucleotides that impaired ribosome biogenesis and, consequently, induced the impaired ribosome biogenesis checkpoint. p53 signaling induced cell cycle arrest and senescence that promoted the survival of GCN2-deficient PCa cells. Depletion of GCN2 combined with loss of p53 or pharmacological inhibition of de novo purine biosynthesis reduced proliferation and enhanced cell death in PCa cell lines, organoids, and xenograft models. Our findings highlight the coordinated interplay between GCN2 and p53 regulation during nutrient stress and provide insight into how they could be targeted in developing new therapeutic strategies for PCa. Editor's summary: The integrated stress response (ISR) enables tumor cells to adapt quickly to their tissue environment, thus supporting cell survival and tumor progression. Cordova et al. found that inhibiting the ISR kinase GCN2 kills prostate cancer cells deficient in the transcription factor p53. GCN2 inhibition decreased the availability of amino acids that are used in purine nucleotide synthesis. In turn, this nucleotide deficiency was survivable only with p53 signaling, which induced cell cycle arrest and senescence. In mice, although inhibiting GCN2 slowed the growth of p53-functional tumors, it did so to a greater extent and induced cell death in p53-deficient tumors. The loss of p53 typically makes killing tumor cells challenging, and these findings indicate a way to take advantage of those mutations. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]

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