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A Specific Role for AKT3 in the Genesis of Ovarian Cancer through Modulation of G₂-M Phase Transition

¹ Growth Control and Differentiation Program; ² Victorian Breast Cancer Research Consortium Cancer Genetics Laboratory; and ³ Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Departments of ⁴ Pathology and ⁵ Biochemistry and Molecular Biology and ⁶ Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia; ⁷ Department of Surgery, University of Melbourne and ⁸ Department of Anatomical Pathology, St. Vincent's Hospital, Fitzroy, Victoria, Australia; and ⁹ Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

Requests for reprints: Richard B. Pearson, Protein Chemistry Laboratory, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, Victoria 8006, Australia. Phone: 61-3-9656-1247; Fax: 61-3-9656-1411; E-mail: rick.pearson{at}petermac.org.

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 G₂-M phase transition. These findings are consistent with AKT3 playing a key role in the genesis of at least one subset of ovarian cancers. (Cancer Res 2006; 66(24): 11718-25)

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