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 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.
Cristiano
Briony E
BE
Growth Control and Differentiation Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Chan
Joanna C
JC
Hannan
Katherine M
KM
Lundie
Nicole A
NA
Marmy-Conus
Nelly J
NJ
Campbell
Ian G
IG
Phillips
Wayne A
WA
Robbie
Melissa
M
Hannan
Ross D
RD
Pearson
Richard B
RB
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
D003470:Culture Media; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt