Regulation of androgen receptor expression through angiotensin II type 1 receptor in prostate cancer cells

BACKGROUND Although the local renin‐angiotensin system (RAS) of the prostate gland is related to cell proliferation and angiogenesis, the detailed mechanism remains unclear. We examined the effects of the angiotensin II type 1 receptor (AT1R) on androgen receptor (AR) expression in prostate cancer cells. METHODS AR modulation by AT1R was examined by Western blot analysis, luciferase assay, and Immunocytochemical staining. The influence of AR expression by angiotensin II (Ang‐II) and AT1R inhibition using siRNA was determined. Furthermore, using angiotensinogen or AT1R knockout (KO) mice, we performed quantitative real‐time PCR to investigate the expression of AR. RESULTS Ang‐II induced cell proliferation with enhancement of AR, prostate specific antigen (PSA), NF‐κB, and c‐myc, and the activity of AR and PSA promoter. Cell proliferation of LNCaP transfected with AT1R siRNA was decreased by 75% at 7 days by inhibition of AR, PSA, NF‐κB, and c‐myc. Immunocytochemical staining confirmed the suppression of AR translocation into the nucleus in AT1R siRNA cells. AT1R KO mice showed a decrease in AR expression in the prostate gland. We also found that the expression level of AT1R could modulate the transcriptional level of AR by affecting NF‐κB and c‐myc expression. CONCLUSIONS Knocking down of the AT1R protein resulted in significant inhibition of cell growth, associated with a marked decrease of AR protein. These results indicate that inhibition of AT1R has the potential to influence AR expression in prostate cells, and is anticipated to contribute to the development of novel therapeutic agents for prostate cancer. Prostate 71: 964–975, 2011. © 2010 Wiley‐Liss, Inc.