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

• DOI: 10.1126/scisignal.adp1375
• Publication Date: 2024-11-26T18:58:10Z
• Authors: Ricardo A. Cordova; Noah R. Sommers; Andrew S. Law; Angela J. Klunk; Katherine E. Brady; David W. Goodrich; Tracy G. Anthony; Jeffrey J. Brault; Roberto Pili; Ronald C. Wek; Kirk A. Staschke
• Keywords: ribosome biogenesis; Integrated stress response; Purine metabolism

Cancers invoke various pathways to mitigate external and internal stresses continue their growth progression. We previously reported that the eIF2 kinase GCN2 integrated stress response are constitutively active in prostate cancer (PCa) required maintain amino acid homeostasis needed fuel tumor growth. However, although loss of function reduces intracellular availability PCa growth, there is no appreciable cell death. Here, we discovered induces prosenescent p53 signaling. This activation occurred through inhibition–dependent reductions purine nucleotides impaired ribosome biogenesis and, consequently, induced checkpoint. signaling cycle arrest senescence promoted survival GCN2-deficient cells. Depletion combined with or pharmacological inhibition de novo biosynthesis reduced proliferation enhanced death lines, organoids, xenograft models. Our findings highlight coordinated interplay between regulation during nutrient provide insight into how they could be targeted developing new therapeutic strategies for PCa.