Inhibition of aberrant androgen receptor induction of prostate specific antigen gene expression, cell proliferation and tumor growth by 17α-estradiol in prostate cancer.
Inhibition of aberrant androgen receptor induction of prostate specific antigen gene expression, cell proliferation and tumor growth by 17α-estradiol in prostate cancer.
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DOI：
10.1016/j.juro.2010.09.008
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发表时间：
2011-01
期刊：
影响因子：
--
通讯作者：
Zhu YS
中科院分区：
文献类型：
--
作者：
Qiao Y;Wang L;Cai LQ;Tan C;Imperato-McGinley J;Zhu YS
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。我们确定了17α-雌二醇（Sigma®）阻断雄激素受体突变引起的雄激素受体异常激活的有效性和机制。我们使用含有突变雄激素受体和野生型雌激素受体β的LNCaP和MDA Pca-2b前列腺肿瘤细胞（ATCC®）来测试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活化的抑制。共转染分析进一步阐明了17α-雌二醇的作用机制。制备具有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）或双氢睾酮诱导的前列腺特异性抗原基因表达产生剂量依赖性抑制。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LNCaP和MDA Pca-2b细胞中双氢睾酮和皮质醇诱导的细胞增殖。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。在患有LNCaP前列腺癌的异种移植小鼠中，17α-雌二醇而不是17β-雌二醇（Sigma）显著抑制肿瘤生长，尽管每种雌激素都倾向于降低肿瘤生长。结果表明，17α-雌二醇具有较低的经典雌激素活性，是一种潜在的治疗雄激素受体突变所致雄激素非依赖性前列腺癌的药物。
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.
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DOI：
10.1158/1078-0432.ccr-08-2660
发表时间：
2009-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Knudsen KE;Scher HI
通讯作者：
Scher HI
DOI：
10.1016/s0006-291x(05)80067-1
发表时间：
1990-12-14
影响因子：
3.1
作者：
VELDSCHOLTE, J;RISSTALPERS, C;MULDER, E
通讯作者：
MULDER, E
影响因子：
3
作者：
Tan, Chen;Cai, Li-Qun;Zhu, Yuan-Shan
通讯作者：
Zhu, Yuan-Shan
影响因子：
4.8
作者：
LEE, C;SUTKOWSKI, DM;KOZLOWSKI, JM
通讯作者：
KOZLOWSKI, JM
影响因子：
2.8
作者：
Arnold, Julia T.;Liu, Xunxian;Blackman, Marc R.
通讯作者：
Blackman, Marc R.