Department of Medicine/Endocrinology, Weill Medical College of Cornell University, New York, New York 10065, USA.
J Urol. 2011 Jan;185(1):305-14. doi: 10.1016/j.juro.2010.09.008.
Androgen independent prostate cancer growth and metastasis are a major cause of prostate cancer death. Aberrant androgen receptor activation due to androgen receptor mutation is an important mechanism of androgen independence. We determined the effectiveness and mechanism of 17α-estradiol (Sigma®) in blocking aberrant androgen receptor activation due to androgen receptor mutation.
We used LNCaP and MDA Pca-2b prostatic tumor cells (ATCC®) containing a mutated androgen receptor and WT estrogen receptor β to test 17α-estradiol inhibition of aberrant androgen receptor activation of prostate specific antigen gene expression and cell growth. Cotransfection analysis was used to further elucidate the mechanism of 17α-estradiol action. Xenograft animals with an LNCaP prostate tumor were prepared to study the in vivo effect of 17α-estradiol on tumor growth inhibition.
In LNCaP cells 17α-estradiol produced a dose dependent inhibition of cyproterone acetate (Sigma) or dihydrotestosterone induced prostate specific antigen gene expression. In MDA Pca-2b cells 17α-estradiol inhibited cortisol (Sigma) induced prostate specific antigen expression and blocked dihydrotestosterone and cortisol induced cell proliferation in LNCaP and MDA Pca-2b cells, respectively. Cotransfection analysis showed that 17α-estradiol inhibition of aberrant androgen receptor activation of prostate specific antigen gene expression was medicated via estrogen receptors. In xenograft mice with LNCaP prostate cancer 17α-estradiol but not 17β-estradiol (Sigma) significantly inhibited tumor growth, although each estrogen tended to decrease tumor growth.
Results suggest that 17α-estradiol with less classic estrogenic activity is a potential therapeutic agent for androgen independent prostate cancer due to androgen receptor mutation.
雄激素非依赖性前列腺癌的生长和转移是前列腺癌死亡的主要原因。雄激素受体突变导致的雄激素受体异常激活是雄激素非依赖性的重要机制。本研究旨在确定 17α-雌二醇（Sigma®）阻断雄激素受体突变导致的雄激素受体异常激活的有效性及其作用机制。
我们使用含有突变型雄激素受体和 WT 雌激素受体β的 LNCaP 和 MDA Pca-2b 前列腺肿瘤细胞（ATCC®）来检测 17α-雌二醇对前列腺特异性抗原基因表达和细胞生长的异常雄激素受体激活的抑制作用。共转染分析用于进一步阐明 17α-雌二醇作用的机制。制备含有 LNCaP 前列腺肿瘤的异种移植动物，以研究 17α-雌二醇对肿瘤生长抑制的体内作用。
在 LNCaP 细胞中，17α-雌二醇对醋酸环丙孕酮（Sigma）或二氢睾酮诱导的前列腺特异性抗原基因表达呈剂量依赖性抑制。在 MDA Pca-2b 细胞中，17α-雌二醇抑制皮质醇（Sigma）诱导的前列腺特异性抗原表达，并分别阻断二氢睾酮和皮质醇诱导的 LNCaP 和 MDA Pca-2b 细胞增殖。共转染分析表明，17α-雌二醇抑制异常雄激素受体激活前列腺特异性抗原基因表达是通过雌激素受体介导的。在含有 LNCaP 前列腺癌的异种移植小鼠中，17α-雌二醇而非 17β-雌二醇（Sigma）显著抑制肿瘤生长，尽管每种雌激素都有降低肿瘤生长的趋势。
结果表明，具有较少经典雌激素活性的 17α-雌二醇可能是一种潜在的治疗雄激素受体突变导致的雄激素非依赖性前列腺癌的药物。
