Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming.

Abstract

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.

• Authors: Raquel Buj, Chi-Wei Chen, Erika S Dahl, Kelly E Leon, Rostislav Kuskovsky, Natella Maglakelidze, Maithili Navaratnarajah, Gao Zhang, Mary T Doan, Helen Jiang, Michael Zaleski, Lydia Kutzler, Holly Lacko, Yiling Lu, Gordon B Mills, Raghavendra Gowda, Gavin P Robertson, Joshua I Warrick, Meenhard Herlyn, Yuka Imamura, Scot R Kimball, David J DeGraff, Nathaniel W Snyder, Katherine M Aird
• Journal: Cell reports (Cell Rep) Vol. 28 Issue 8 Pg. 1971-1980.e8 (08 20 2019) ISSN: 2211-1247 [Electronic] United States
• PMID: 31433975 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• Nucleotides
• Mechanistic Target of Rapamycin Complex 1
• Aldose-Ketose Isomerases
• ribosephosphate isomerase

Topics

• Aldose-Ketose Isomerases (metabolism)
• Animals
• Cell Line
• Cellular Senescence
• Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
• Gene Knockdown Techniques
• Humans
• Male
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Mice, SCID
• Nucleotides (metabolism)
• Pentose Phosphate Pathway
• Protein Biosynthesis