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

Autor:	Cordova RA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA., Sommers NR; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA., Law AS; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Indiana Center for Musculoskeletal Health, Indianapolis, IN 46202, USA., Klunk AJ; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Brady KE; Department of Biology, Indiana University School of Science, Indianapolis, IN 46202, USA., Goodrich DW; Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA., Anthony TG; Department of Nutritional Sciences and the New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ 08901, USA., Brault JJ; Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Indiana Center for Musculoskeletal Health, Indianapolis, IN 46202, USA., Pili R; Jacobs School of Medicine and Biomedical Sciences, Division of Hematology and Oncology, University at Buffalo, Buffalo, NY 14203, USA., Wek RC; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA., Staschke KA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2024 Nov 26; Vol. 17 (864), pp. eadp1375. Date of Electronic Publication: 2024 Nov 26.
DOI:	10.1126/scisignal.adp1375
Abstrakt:	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.
Databáze:	MEDLINE
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