Department of Urology Research/Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Prostate. 2010 Jun 15;70(9):959-70. doi: 10.1002/pros.21130.
Deregulated androgen receptor (AR) action is critical for prostate cancer (PCa) progression. Aberrant expression of AR-associated coregulators contributes to AR activity in PCa. The mechanisms underlying coregulator expression in PCa are under intense investigation as they may lead to alternative means of targeting AR activity in PCa cells. We have recently shown that over 30% of coregulator expression in the PCa cell line LNCaP is subject to androgen regulation.
Using multiple PCa cell lines as well as xenograft models, non-malignant prostate epithelial cell lines and androgen-responsive tissues derived from a male Wistar rat model system, we explored the effect of androgen stimulation and androgen deprivation on the expression of the core coactivators SRC1, SRC2, SRC3, CBP, and p300.
Androgen stimulation of model systems representing PCa led to a decrease in the expression of SRC1, SRC2, SRC3, CBP, and p300, whereas androgen deprivation induced the expression of these coactivators. In contrast, expression of these coregulators remained largely unaffected following changes in the androgenic milieu in AR-positive models representing non-malignant prostate cells and tissues.
Our data indicate differences in the regulation of coregulator expression between neoplastic and normal prostate cells. These findings emphasize the important potential of targeting the mechanisms regulating coregulator expression for therapeutic intervention in PCa.
去调控的雄激素受体 (AR) 作用对前列腺癌 (PCa) 的进展至关重要。AR 相关共激活因子的异常表达有助于 PCa 中的 AR 活性。由于它们可能导致靶向 PCa 细胞中 AR 活性的替代方法，因此正在深入研究共激活因子在 PCa 中的表达机制。我们最近表明，超过 30%的 LNCaP PCa 细胞系中的共激活因子表达受到雄激素的调控。
使用多个 PCa 细胞系以及异种移植模型、非恶性前列腺上皮细胞系和来自雄性 Wistar 大鼠模型系统的雄激素反应组织，我们研究了雄激素刺激和雄激素剥夺对共激活因子 SRC1、SRC2、SRC3、CBP 和 p300 的表达的影响。
雄激素刺激代表 PCa 的模型系统导致 SRC1、SRC2、SRC3、CBP 和 p300 的表达减少，而雄激素剥夺诱导这些共激活因子的表达。相比之下，在代表非恶性前列腺细胞和组织的 AR 阳性模型中，雄激素环境的变化对这些共调节剂的表达影响不大。
我们的数据表明，肿瘤和正常前列腺细胞中调节共激活因子表达的机制存在差异。这些发现强调了靶向调节共激活因子表达的机制在治疗 PCa 方面的重要潜力。
