The adrenal androgen Androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor
The adrenal androgen Androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor
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DOI：
10.1158/0008-5472.can-03-0130
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发表时间：
2004-01-15
期刊：
影响因子：
11.2
通讯作者：
Namiki, M
中科院分区：
文献类型：
--
作者：
Mizokami, A;Koh, E;Namiki, M
尽管对雄激素剥夺疗法有初始反应，但前列腺癌（PCa）最终从雄激素依赖性表型进展为雄激素非依赖性表型。雄激素受体（AR）第877位氨基酸突变引起抗雄激素戒断现象是复发的机制之一。本研究建立了一种测定前列腺组织中雄烯二醇浓度的方法。我们发现，即使在雄激素剥夺治疗后，前列腺癌组织中的阿迪奥仍保持高浓度。此外，二醇是LNCaP PCa细胞中突变型AR的2种更强的激活剂，并且比双氢睾酮（DHT）诱导更多的细胞增殖、前列腺特异性抗原（PSA）mRNA表达和PSA启动子。由于抗雄激素比卡鲁胺阻断了LNCaP细胞中的adiol活性，因此表明adiol效应是通过AR介导的。然而，高浓度的比卡鲁胺是完全阻断二醇活性所必需的。它们的作用是特异性的LNCaP细胞，因为diol在转染野生型AR的PC-3 PCa细胞中的作用小于DHT，而在转染突变型AR的PC-3细胞中具有相似的作用。在LNCaP细胞中，adiol激活突变型AR的机制不是由于对突变型AR的亲和力增加，也不是由于AR与辅激活因子ARA 70的结合。然而，低浓度的diol诱导更多的AR核转位比DHT在LNCaP细胞，而不是PC-3细胞转染AR。这些结果表明，即使在激素治疗后，阿迪奥也可能导致PCa的进展。
Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse h antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is 2 stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. Them effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR's association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.