title: Activation of the PIK3CA/AKT pathway suppresses senescence induced by an activated RAS oncogene to promote tumorigenesis.
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.
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA 19129, USA; Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Alyssa L
authors.initials: AL
authors.lastname: Kennedy
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.forename: Indrani
authors.initials: I
authors.lastname: Manoharan
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.forename: Nigel B
authors.initials: NB
authors.lastname: Jamieson
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Pawlikowski
authors.forename: Tony
authors.initials: T
authors.lastname: McBryan
authors.forename: Brendan
authors.initials: B
authors.lastname: Doyle
authors.forename: Colin
authors.initials: C
authors.lastname: McKay
authors.forename: Karin A
authors.initials: KA
authors.lastname: Oien
authors.forename: Greg H
authors.initials: GH
authors.lastname: Enders
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
mesh_terms: D000368:Aged; D000818:Animals; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse