Mutant p53 and mTOR/PKM2 regulation in cancer cells

IUBMB Life. 2016 Sep;68(9):722-6. doi: 10.1002/iub.1534. Epub 2016 Jul 7.

Abstract

Mutations of TP53 gene are the most common feature in aggressive malignant cells. In addition to the loss of the tumor suppressive role of wild-type p53, hotspot mutant p53 isoforms display oncogenic proprieties notoriously referred as gain of functions (GOFs) which result in chemoresistance to therapies, genomic instability, aberrant deregulation of cell cycle progression, invasiveness and enhanced metastatic potential, and finally, in patient poor survival rate. The identification of novel functional oncogenic pathways regulated by mutant p53 represent and intriguing topic for emerging therapies against a broad spectrum of cancer types bearing mutant TP53 gene. Mammalian target of rapamycin (mTOR), as well as pyruvate kinase isoform M2 (PKM2) are master regulators of cancer growth, metabolism, and cell proliferation. Herein, we report that GOF mutant R175H and R273H p53 proteins trigger PKM2 phosphorylation on Tyr 105 through the involvement of mTOR signaling. Our data, together with the newly discovered connection between mutant p53 and mTOR stimulation, raise important implications for the potential therapeutic use of synthetic drugs inhibiting mTOR/PKM2 axis in cancer cells bearing mutant TP53 gene. We further hypothesize that mTOR/PKM2 pathway stimulation serves to sustain the oncogenic activity of mutant p53 through both the enhancement of chemoresistance and of aerobic glycolysis of cancer cells. © 2016 IUBMB Life, 68(9):722-726, 2016.

Keywords: PKM2; cancer; chemoresistance; mTOR; mutant p53.

MeSH terms

  • Carrier Proteins / genetics*
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Glycolysis
  • Humans
  • Membrane Proteins / genetics*
  • Mutation
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Phosphorylation
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics*
  • Thyroid Hormones / genetics*
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Carrier Proteins
  • Membrane Proteins
  • TP53 protein, human
  • Thyroid Hormones
  • Tumor Suppressor Protein p53
  • thyroid hormone-binding proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases