2. Academic Validation
  3. Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming

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

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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