A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition

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 f...

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Published inCancer research (Chicago, Ill.) Vol. 66; no. 24; p. 11718
Main Authors Cristiano, Briony E, Chan, Joanna C, Hannan, Katherine M, Lundie, Nicole A, Marmy-Conus, Nelly J, Campbell, Ian G, Phillips, Wayne A, Robbie, Melissa, Hannan, Ross D, Pearson, Richard B
Format Journal Article
LanguageEnglish
Published United States 15.12.2006
Subjects
Cell Division
Culture Media
Female
G2 Phase
Glutathione Transferase - metabolism
Humans
Kidney
Kinetics
Ovarian Neoplasms - genetics
Ovarian Neoplasms - pathology
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Recombinant Fusion Proteins - metabolism
RNA Interference
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Summary: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.
ISSN:0008-5472
DOI:10.1158/0008-5472.CAN-06-1968