Activation of the PIK3CA/AKT pathway suppresses senescence induced by an activated RAS oncogene to promote tumorigenesis

Mol Cell. 2011 Apr 8;42(1):36-49. doi: 10.1016/j.molcel.2011.02.020.

Abstract

Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. Moreover, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. In vivo, bypass of RAS-induced senescence by activated PIK3CA/AKT correlates with accelerated tumorigenesis. Thus, not all oncogenes are equally potent inducers of senescence, and, paradoxically, a weak inducer of senescence (PIK3CA/AKT) can be dominant over a strong inducer of senescence (RAS). For tumor growth, one selective advantage of concurrent mutation of RAS and PTEN/PIK3CA/AKT is suppression of RAS-induced senescence. Evidence is presented that this new understanding can be exploited in rational development and targeted application of prosenescence cancer therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cell Line, Transformed
  • Cell Proliferation
  • Cellular Senescence / genetics
  • Cellular Senescence / physiology
  • Class I Phosphatidylinositol 3-Kinases
  • Disease Models, Animal
  • Enzyme Activation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, ras*
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Middle Aged
  • Mutation
  • Neoplasms / enzymology*
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • PTEN Phosphohydrolase / antagonists & inhibitors
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction

Substances

  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse