Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming

Abstract

Summary: Reprogrammed metabolism and cell cycle dysregulation are two cancer hallmarks. p16 is a cell cycle inhibitor and tumor suppressor that is upregulated during oncogene-induced senescence (OIS). Loss of p16 allows for uninhibited cell cycle progression, bypass of OIS, and tumorigenesis. Whether p16 loss affects pro-tumorigenic metabolism is unclear. We report that suppression of p16 plays a central role in reprogramming metabolism by increasing nucleotide synthesis. This occurs by activation of mTORC1 signaling, which directly mediates increased translation of the mRNA encoding ribose-5-phosphate isomerase A (RPIA), a pentose phosphate pathway enzyme. p16 loss correlates with activation of the mTORC1-RPIA axis in multiple cancer types. Suppression of RPIA inhibits proliferation only in p16-low cells by inducing senescence both in vitro and in vivo. These data reveal the molecular basis whereby p16 loss modulates pro-tumorigenic metabolism through mTORC1-mediated upregulation of nucleotide synthesis and reveals a metabolic vulnerability of p16-null cancer cells. : Senescence bypass through p16 loss predisposes to transformation and tumorigenesis. Buj et al. found that the loss of p16 upregulates nucleotide metabolism through increased mTORC1-mediated translation of RPIA to bypass senescence in an RB-independent manner. Thus, the mTORC1-RPIA axis is a metabolic vulnerability for p16-null cancers. Keywords: cancer metabolism, ribonucleotide reductase M2, BRAF, cell cycle, senescence, melanoma, pancreatic cancer, nevi, pentose phosphate pathway, ribose-5-phosphate isomerase A