title: A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition.
abstract: Ovarian cancer is the major cause of death from gynecological malignancy, and there is an urgent need for new therapeutic targets. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been strongly implicated in the genesis of ovarian cancer. However, to identify and evaluate potential targets for therapeutic intervention, it is critical to understand the mechanism by which the PI3K/AKT pathway facilitates ovarian carcinogenesis. Here, we show that AKT3 is highly expressed in 19 of 92 primary ovarian tumors. Strikingly, purified AKT3 exhibited up to 10-fold higher specific activity than AKT1, potentially amplifying the effects of AKT3 overexpression. Consistent with this finding, AKT3 levels in a range of ovarian cancer cell lines correlated with total AKT activity and proliferation rates, implicating AKT3 as a key mediator of ovarian oncogenesis. Specific silencing of AKT3 using short hairpin RNA markedly inhibited proliferation of the two cell lines with highest AKT3 expression and total AKT activity, OVCA429 and DOV13, by slowing G(2)-M phase transition. These findings are consistent with AKT3 playing a key role in the genesis of at least one subset of ovarian cancers.
authors.affiliation: Growth Control and Differentiation Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Briony E
authors.initials: BE
authors.lastname: Cristiano
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Chan
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Hannan
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Lundie
authors.forename: Nelly J
authors.initials: NJ
authors.lastname: Marmy-Conus
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.forename: Melissa
authors.initials: M
authors.lastname: Robbie
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
mesh_terms: D002455:Cell Division; D003470:Culture Media; D005260:Female; D016195:G2 Phase; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007668:Kidney; D007700:Kinetics; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism
chemical_list: D003470:Culture Media; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt