Zhu Yuan-Shan, Cai Li-Qun, Huang Ying, Fish Jason, Wang Lu, Zhang Zhi-Kai, Imperato-McGinley Julianne L
Department of Medicine/Endocrinology, Weill Medical College of Cornell University, 1300 York Ave, Box 149, New York, NY 10021, USA.
J Androl. 2005 Jul-Aug;26(4):500-8; discussion 509-10. doi: 10.2164/jandrol.05002.
Androgens via the androgen receptor (AR) play crucial roles in prostate physiology and pathophysiology. These androgen actions can be either inhibited or potentiated by estrogens. The mechanisms of these seemingly opposing estrogen effects are unclear. We studied the effects of estrogens on the modulation of androgen induction of prostate specific antigen (PSA) gene expression and prostate tumor cell growth. Cotransfection analyses in CV-1, DU-145, and PC-3 cells showed that dihydrotestosterone (DHT)-induced PSA transcription activity was inhibited by 17beta-estradiol, diethylstilbestrol, ICI182780, and 17alpha-estradiol, but not by tamoxifen via estrogen receptor alpha (ERalpha). In the presence of ERbeta, 17beta-estradiol and diethylstilbestrol had no significant effect, while 17alpha-estradiol inhibited and ICI182780 and tamoxifen potentiated DHT action. When both ERalpha and ERbeta were present, all ER-ligands except tamoxifen inhibited DHT action. The inhibition of DHT action by 17beta-estradiol via ERalpha was mainly dependent on the DNA binding domain, while the 17alpha-estradiol effect was mainly dependent on the ERalpha carboxyl terminus. Treatment with DHT in LAPC-4 prostate tumor cells that express a wild-type AR and both ERbeta and ERalpha greatly increased the PSA gene expression and cell growth. These DHT effects were significantly attenuated by the addition of 17alpha-estradiol, 17beta-estradiol, or cyproterone acetate in a dose-dependent manner. These results indicate that estrogens produce an ER-isoform- and ER-ligand-specific modulation of DHT induction of PSA gene expression and prostate tumor cell growth, providing a molecular basis for designing favorable agents for the prevention and control of prostate cancer.
雄激素通过雄激素受体（AR）在前列腺生理和病理生理过程中发挥关键作用。这些雄激素作用可被雌激素抑制或增强。这些看似相反的雌激素作用机制尚不清楚。我们研究了雌激素对雄激素诱导前列腺特异性抗原（PSA）基因表达及前列腺肿瘤细胞生长的调节作用。在CV-1、DU-145和PC-3细胞中的共转染分析表明，双氢睾酮（DHT）诱导的PSA转录活性受到17β-雌二醇、己烯雌酚、ICI182780和17α-雌二醇的抑制，但他莫昔芬通过雌激素受体α（ERα）未产生抑制作用。在存在ERβ的情况下，17β-雌二醇和己烯雌酚无显著作用，而17α-雌二醇具有抑制作用，ICI182780和他莫昔芬则增强DHT的作用。当ERα和ERβ同时存在时，除他莫昔芬外的所有ER配体均抑制DHT的作用。17β-雌二醇通过ERα对DHT作用的抑制主要依赖于DNA结合结构域，而17α-雌二醇的作用主要依赖于ERα羧基末端。在表达野生型AR以及ERβ和ERα的LAPC-4前列腺肿瘤细胞中用DHT处理，可显著增加PSA基因表达和细胞生长。添加17α-雌二醇、17β-雌二醇或醋酸环丙孕酮可剂量依赖性地显著减弱这些DHT的作用。这些结果表明，雌激素对DHT诱导的PSA基因表达和前列腺肿瘤细胞生长产生ER异构体和ER配体特异性调节，为设计预防和控制前列腺癌的有利药物提供了分子基础。
