Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming

• Published in: Cell reports (Cambridge) Vol. 28; no. 8; pp. 1971 - 1980.e8
• Main Authors: Buj, Raquel, Chen, Chi-Wei, Dahl, Erika S., Leon, Kelly E., Kuskovsky, Rostislav, Maglakelidze, Natella, Navaratnarajah, Maithili, Zhang, Gao, Doan, Mary T., Jiang, Helen, Zaleski, Michael, Kutzler, Lydia, Lacko, Holly, Lu, Yiling, Mills, Gordon B., Gowda, Raghavendra, Robertson, Gavin P., Warrick, Joshua I., Herlyn, Meenhard, Imamura, Yuka, Kimball, Scot R., DeGraff, David J., Snyder, Nathaniel W., Aird, Katherine M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-08-2019; Elsevier
• Subjects: Aldose-Ketose Isomerases - metabolism; Animals; BRAF; cancer metabolism; cell cycle; Cell Line; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Gene Knockdown Techniques; Humans; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; melanoma; Mice, SCID; nevi; Nucleotides - metabolism; pancreatic cancer; Pentose Phosphate Pathway; Protein Biosynthesis; ribonucleotide reductase M2; ribose-5-phosphate isomerase A; senescence; cancer metabolism; senescence; pancreatic cancer; cell cycle; melanoma; nevi; BRAF; pentose phosphate pathway; ribonucleotide reductase M2; ribose-5-phosphate isomerase A
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.084

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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•p16 knockdown activates mTORC1 to increase nucleotide synthesis and bypass senescence•mTORC1 directly increases translation of RPIA to increase ribose-5-phosphate•Activation of the mTORC1 pathway downstream of p16 suppression is independent of RB•RPIA suppression induces senescence only in cells and tumors with low p16
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.