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Androgens Transduce the Gs-Mediated Activation of Protein Kinase A in Prostate Cells

Department of Pathology, Medical College of Georgia, Augusta, Georgia

Requests for reprints: Yehia Daaka, Department of Pathology, CN3114, Medical College of Georgia, Augusta, GA 30912. Phone: 706-721-8214; Fax: 706-721-8873; E-mail: ydaaka{at}mcg.edu.

Key Words: G protein • protein kinase A • androgen receptor • testosterone • prostate cancer

Androgens regulate the development and function of male reproductive organs and play a crucial role in the onset and progression of prostate cancer. Androgen action is primarily mediated through the nuclear androgen receptor (AR) which acts as a ligand-dependent transcription factor. This mode of androgen action takes hours to manifest and is called the genomic pathway. The androgen-mediated genomic responses require activity of cyclic AMP (cAMP)-dependent protein kinase (PKA). Androgens also act through nongenomic pathways in certain cell types to evoke rapid responses (manifested in minutes) that are mediated through changes in ion currents and second messengers. Here, we show that androgen causes the rapid and cAMP-dependent activation of PKA in prostate cells. The androgen-induced PKA activation is not inhibited by nuclear AR antagonist bicalutamide and can be observed in cells that do not express nuclear AR gene. Reduction of Gs expression with siRNA attenuates the androgen-mediated activation of PKA, which is required for the androgen-induced prostate cell proliferation. We conclude that androgen actively evokes a nongenomic signaling pathway to activate PKA that is needed for the genomic functioning of nuclear AR. The inhibition of PKA activation, together with standard AR-targeted therapies, may be more efficacious for treatment of patients with prostate cancer. [Cancer Res 2008;68(9):3225–31]

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