Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP
Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP
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DOI：
10.1093/carcin/22.9.1399
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发表时间：
2001-09-01
期刊：
影响因子：
4.7
通讯作者：
Young, CYF
中科院分区：
文献类型：
--
作者：
Zhu, W;Zhang, JS;Young, CYF
许多报告表明，多酚类黄酮水飞蓟素（SM）是一种有效的抗癌剂。具有阻断雄激素受体（AR）功能的新机制的药物可能有助于前列腺癌的预防和治疗。先前的研究表明，SM 的主要活性成分水飞蓟宾 (SB) 可以通过将细胞周期阻滞在 G(1) 期来抑制人前列腺癌细胞系 LNCaP 的细胞增殖，而不导致细胞死亡。这项研究进一步阐明了 SM 和 SB 通过抑制 AR 功能而对雄激素反应性前列腺癌细胞表现出抗增殖作用的潜在分子机制。我们观察到 SM 和 SB 抑制雄激素刺激的细胞增殖以及雄激素刺激的前列腺特异性抗原 (PSA) 和人腺激肽释放酶 (hK2) 的分泌。此外，我们首次证明亲免素 FKBP51 受雄激素调节，并且这种上调受到 SM 和 SB 的抑制。我们进一步证明，使用 PSA 启动子和 hK2 雄激素响应元件构建体的基因转移，SM 和 SB 可以减弱 AR 的反式激活活性。然而，在蛋白质印迹和配体结合测定中，总 AR 的表达和类固醇结合能力不受 SM 的影响。有趣的是，我们使用蛋白质印迹分析和免疫细胞化学染色发现，在雄激素存在的情况下，SM 和 SB 显着降低了核 AR 水平。这项研究为 SM 和 SB 如何负调节前列腺癌细胞中的雄激素作用提供了新的见解。
A number of reports have shown that the polyphenolic flavonoid silymarin (SM) is an effective anticancer agent. Agents with novel mechanisms of blocking androgen receptor (AR) function may be useful for prostate cancer prevention and therapy. Previous studies showed that silibinin (SB), the major active component of SM, could inhibit cell proliferation of a human prostate cancer cell line, LNCaP, by arresting the cell cycle at the G(1) phase without causing cell death. This study further delineates the potential molecular mechanism by which SM and SB exhibit antiproliferative effects on androgen-responsive prostate cancer cells by inhibiting function of the AR. We observed that SM and SB inhibited androgen-stimulated cell proliferation as well as androgen-stimulated secretion of both prostate-specific antigen (PSA) and human glandular kallikrein (hK2). Additionally, for the first time, we show that an immunophilin, FKBP51, is androgen regulated and that this up-regulation is suppressed by SM and SB. We further demonstrate that transactivation activity of the AR was diminished by SM and SB using gene transfer of PSA promoter and hK2 androgen-responsive element constructs. However, expression and steroid-binding ability of total AR were not affected by SM in western blotting and ligand-binding assays. Intriguingly, we found that nuclear AR levels are significantly reduced by SM and SB in the presence of androgens using western blotting assay and immunocytochemical staining. This study provides a new insight into how SM and SB negatively modulate androgen action in prostate cancer cells.