Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming

  • Cell Rep. 2019 Aug 20;28(8):1971-1980.e8. doi: 10.1016/j.celrep.2019.07.084.
Raquel Buj  1 ,  Chi-Wei Chen  1 ,  Erika S Dahl  1 ,  Kelly E Leon  1 ,  Rostislav Kuskovsky  2 ,  Natella Maglakelidze  3 ,  Maithili Navaratnarajah  1 ,  Gao Zhang  4 ,  Mary T Doan  2 ,  Helen Jiang  2 ,  Michael Zaleski  5 ,  Lydia Kutzler  1 ,  Holly Lacko  1 ,  Yiling Lu  6 ,  Gordon B Mills  7 ,  Raghavendra Gowda  8 ,  Gavin P Robertson  8 ,  Joshua I Warrick  5 ,  Meenhard Herlyn  4 ,  Yuka Imamura  8 ,  Scot R Kimball  1 ,  David J DeGraff  5 ,  Nathaniel W Snyder  2 ,  Katherine M Aird  9
Affiliations
  • 1. Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA.
  • 2. A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA 19104, USA.
  • 3. MSTP Program, Penn State College of Medicine, Hershey, PA 17033, USA.
  • 4. Molecular and Cellular Oncogenesis Program and Melanoma Research Institute, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 5. Department of Pathology, Penn State College of Medicine, Hershey, PA 17033, USA.
  • 6. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 7. Department of Cell, Developmental & Cancer Biology, Oregon Health and Sciences University, Portland, OR 97201, USA.
  • 8. Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA.
  • 9. Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA. Electronic address: [email protected].
PMID: 31433975 DOI: 10.1016/j.celrep.2019.07.084
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.

Keywords
BRAF; cancer metabolism; cell cycle; melanoma; nevi; pancreatic cancer; pentose phosphate pathway; ribonucleotide reductase M2; ribose-5-phosphate isomerase A; senescence.
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