Abstract:
Prostate Cancer is one of the most common malignancies in the US. Activation of androgen receptor (AR) has been shown to play a critical role in the initiation, maintenance and progression of prostate cancer. In an attempt to identify novel components of androgen signaling pathway leading to AR transactivation, we investigated the involvement of G-protein a-subunits in AR transactivation using androgen-responsive luciferase (ARE-LUC) reporter assay. Overexpressing Ga proteins such as Ga12, Gas, Gai, Gaq showed various effect on the basal activity or a physiological level of androgen (R1881)-induced ARE-LUC reporter activities. Only Gas enhanced the basal activity of the reporter. Active Gq significantly reduced androgen-induced ARE-LUC reporter activity, but active Ga12 and Gas enhanced reporter activities. In siRNA-mediated knockdown experiments, we found that siRNAs against Ga12 and Gas reduced R1881-induced ARE-LUC reporter activities while siRNAs for Gai and Gaq showed less effect. Finally, we found that treatment with Ga12 and Gas siRNAs abolished androgen-induced PI3K (phosphoinositide 3-OH kinase) activation, which was required for AR transactivation. More studies involving G proteins and PI3K are undertaken to further elucidate the mechanism of AR transactivation.
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