Journal
CELL REPORTS
Volume 28, Issue 8, Pages 1971-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.07.084
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Funding
- NIH [F31CA236372, P50CA174523, U54CA224070, R01DK13499, R01K156548, K22ES026235, R01GM132261, R00CA194309]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- W.W. Smith Charitable Trust
- Penn State Cancer Institute Postdoctoral Fellowship
- NCI [P30CA16672]
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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.
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