Desiniotis A, Schäfer G, Klocker H, Eder IE
Enhanced anti-proliferative and pro-apoptotic effects on prostate cancer cells by simultaneously inhibiting androgen receptor and cAMP dependent protein kinase A. [JOURNAL ARTICLE]
Int J Cancer 2009 Aug 3.
The androgen signaling pathway with the androgen receptor (AR) as its key molecule is widely understood to influence prostate tumor growth significantly even after androgen ablation. Under androgen-deprived conditions, the AR may be activated inappropriately through interaction with other molecules, including cAMP dependent protein kinase A (PKA). In a previous study we have shown that knocking down the AR significantly inhibits prostate tumor growth. In this study, we show that combined inhibition of the androgen receptor and the regulatory subunit I alpha of protein kinase A (PKA RIalpha) with small interference RNAs significantly increased the growth-inhibitory and pro-apoptotic effects of AR knockdown. This treatment strategy was effective in androgen sensitive and in androgen ablation resistant prostate cancer cells. In addition, we report that downregulating PKA RIalpha was sufficient to inhibit PKA signaling and interestingly also impaired AR expression and activation. Vice versa, AR knockdown induced a decline in PKA RIalpha, associated with reduced PKA activity. This mutual influence on expression level was specific since downregulation of AR did not affect expression of PKA RIalpha in AR negative DU-145 cells and an siRNA control did not affect protein expression. Another important finding of our study was that depletion of PKA RIalpha also potentiated the anti-proliferative effect of the antiandrogen bicalutamide in androgen sensitive LNCaP. We therefore concluded that combined inhibition of PKA RIalpha and AR may be a promising new therapeutic option for prostate cancer patients and might be superior to solely preventing AR expression. (c) 2009 UICC.
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