Activation of the Androgen Receptor by Intratumoral Bioconversion of Androstanediol to Dihydrotestosterone in Prostate Cancer
Activation of the Androgen Receptor by Intratumoral Bioconversion of Androstanediol to Dihydrotestosterone in Prostate Cancer
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DOI：
10.1158/0008-5472.can-10-1343
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发表时间：
2011-02-15
期刊：
影响因子：
11.2
通讯作者：
Wilson, Elizabeth M.
中科院分区：
文献类型：
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作者：
Mohler, James L.;Titus, Mark A.;Wilson, Elizabeth M.
雄激素受体（AR）响应二氢睾酮（DHT）介导良性和恶性前列腺的生长。在接受前列腺癌雄激素剥夺治疗的患者中，尽管睾丸雄激素循环水平较低且肾上腺雄激素水平正常，但 AR 仍会促进前列腺癌生长。在本报告中，我们证明了在前列腺来源的细胞系中存在 5 α-雄甾烷-3 α,17 β-二醇（雄甾烷二醇）时 AR 反式激活的程度与雄甾烷二醇向 DHT 的生物转化平行。前列腺癌细胞系中雄甾烷二醇存在时的 AR 反式激活主要与 17β-羟基类固醇脱氢酶 6 (17β-HSD6) 的 mRNA 和蛋白质水平相关，17β-HSD6 是雄甾烷二醇相互转化为 DHT 和无活性代谢物雄酮所需的几种酶之一。视黄醇脱氢酶 5 和脱氢酶/还原酶短链脱氢酶/还原酶家族成员 9（也将雄甾烷二醇转化为 DHT）的水平低于前列腺来源的细胞系中的 17 beta-HSD6，而在去势复发的人前列腺癌异种移植物中水平较高。使用质谱法测量组织雄烷二醇，证明雄烷二醇代谢为 DHT 和雄酮。将雄烷二醇二丙酸酯给予去势复发性 CWR22R 肿瘤的无胸腺去势雄性小鼠，可使瘤内 DHT 水平增加 28 倍。在雄烷二醇存在的情况下，前列腺癌细胞中的 AR 反式激活是由雄烷二醇细胞特异性转化为 DHT 引起的，并且雄烷二醇增加了 LAPC-4 细胞的生长。将雄甾烷二醇转化为 DHT 的能力提供了一种最佳利用雄激素前体和分解代谢物进行 DHT 合成的机制。癌症研究； 71(4)； 1486-96。 (c) 2011 年 AACR。
The androgen receptor (AR) mediates the growth of benign and malignant prostate in response to dihydrotestosterone (DHT). In patients undergoing androgen deprivation therapy for prostate cancer, AR drives prostate cancer growth despite low circulating levels of testicular androgen and normal levels of adrenal androgen. In this report, we demonstrate the extent of AR transactivation in the presence of 5 alpha-androstane-3 alpha,17 beta-diol (androstanediol) in prostate-derived cell lines parallels the bioconversion of androstanediol to DHT. AR transactivation in the presence of androstanediol in prostate cancer cell lines correlated mainly with mRNA and protein levels of 17 beta-hydroxysteroid dehydrogenase 6 (17 beta-HSD6), one of several enzymes required for the interconversion of androstanediol to DHT and the inactive metabolite androsterone. Levels of retinol dehydrogenase 5, and dehydrogenase/reductase short-chain dehydrogenase/reductase family member 9, which also convert androstanediol to DHT, were lower than 17 beta-HSD6 in prostate-derived cell lines and higher in the castration-recurrent human prostate cancer xenograft. Measurements of tissue androstanediol using mass spectrometry demonstrated androstanediol metabolism to DHT and androsterone. Administration of androstanediol dipropionate to castration-recurrent CWR22R tumor-bearing athymic castrated male mice produced a 28-fold increase in intratumoral DHT levels. AR transactivation in prostate cancer cells in the presence of androstanediol resulted from the cell-specific conversion of androstanediol to DHT, and androstanediol increased LAPC-4 cell growth. The ability to convert androstanediol to DHT provides a mechanism for optimal utilization of androgen precursors and catabolites for DHT synthesis. Cancer Res; 71(4); 1486-96. (c) 2011 AACR.