Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Prostate. 2011 Jun 15;71(9):964-75. doi: 10.1002/pros.21312. Epub 2010 Dec 28.
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.
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.
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.
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.
尽管前列腺局部肾素-血管紧张素系统（RAS）与细胞增殖和血管生成有关，但详细机制尚不清楚。我们研究了血管紧张素 II 型 1 型受体（AT1R）对前列腺癌细胞中雄激素受体（AR）表达的影响。
通过 Western blot 分析、荧光素酶测定和免疫细胞化学染色检测 AT1R 对 AR 的调节作用。用血管紧张素 II（Ang-II）和 siRNA 抑制 AT1R 测定 AR 表达的影响。此外，使用血管紧张素原或 AT1R 敲除（KO）小鼠，通过定量实时 PCR 研究 AR 的表达。
Ang-II 诱导细胞增殖，增强 AR、前列腺特异性抗原（PSA）、NF-κB 和 c-myc 以及 AR 和 PSA 启动子的活性。转染 AT1R siRNA 的 LNCaP 细胞的细胞增殖在 7 天时因 AR、PSA、NF-κB 和 c-myc 的抑制而减少了 75%。免疫细胞化学染色证实 AT1R siRNA 细胞中 AR 向核内易位受到抑制。AT1R KO 小鼠前列腺中 AR 表达减少。我们还发现 AT1R 的表达水平可通过影响 NF-κB 和 c-myc 的表达来调节 AR 的转录水平。
敲低 AT1R 蛋白可显著抑制细胞生长，伴随 AR 蛋白明显减少。这些结果表明，抑制 AT1R 有可能影响前列腺细胞中的 AR 表达，并有望为前列腺癌的新型治疗药物的开发做出贡献。
