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 occurred via Ataxia Telangiectasia and Rad3-Related Protein (ATR) activation of mTORC1 signaling, which mediated increased translation of the mRNA encoding ribose-5-phosphate isomerase A (RPIA), a pentose phosphate pathway enzyme. p16 loss correlated with activation of the ATR-mTORC1-RPIA axis in multiple cancer types. Suppression of RPIA inhibited proliferation of cancer cells only with low p16 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-low cancer cells.
Highlights
Suppression of p16 activates the ATR-mTORC1 signaling axis to increase nucleotide synthesis
Low p16 expression increases sensitivity to mTORC1 inhibition
mTORC1 increases translation of the mRNA encoding the pentose phosphate pathway enzyme ribose-5-phosphate isomerase A (RPIA)
RPIA suppression induces senescence only in cancer cells with low p16