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

Kennedy AL, Morton JP, Manoharan I, Nelson DM, Jamieson NB, Pawlikowski JS, McBryan T, Doyle B, McKay C, Oien KA, Enders GH, Zhang R, Sansom OJ, Adams PD
Mol Cell. 2011 42 (1): 36-49

PMID: 21474066 · PMCID: PMC3145340 · DOI:10.1016/j.molcel.2011.02.020

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.

Copyright © 2011 Elsevier Inc. All rights reserved.

MeSH Terms (24)

Aged Animals Cell Line, Transformed Cell Proliferation Cellular Senescence 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 Pancreatic Neoplasms Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase Signal Transduction

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