The androgen receptor can signal through Wnt/beta-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens.
The androgen receptor can signal through Wnt/beta-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens.
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雄激素受体可以通过前列腺癌细胞中的Wnt/β-catenin发出信号，作为适应雄激素水平的适应机制。
DOI：
10.1186/1471-2121-9-4
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发表时间：
2008-01-24
期刊：
影响因子：
--
通讯作者：
Attar, Ricardo M.
中科院分区：
文献类型：
--
作者：
Schweizer, Liang;Rizzo, Cheryl A.;Spires, Thomas E.;Platero, J. Suso;Wu, Qiuyan;Lin, Tai-An;Gottardis, Marco M.;Attar, Ricardo M.
前列腺癌进展中的一个关键事件是从激素敏感的疾病状态转变为激素抵抗的疾病状态。与这一转变相关的是，雄激素受体(AR)扩增和突变经常在激素消融治疗失败的患者中观察到。β-连环蛋白是典型的Wnt信号通路的重要组成部分，在雄激素存在的情况下，它是AR信号的共激活因子。然而，目前还不清楚AR水平的增加会对这些激素不敏感的前列腺细胞中的Wnt信号通路产生什么影响。瞬时转染人前列腺癌细胞株的结果表明，AR过表达可增强Wnt/β-catenin信号通路的转录活性。此外，在雄激素去势水平上，Wnt信号通路的同时激活和AR的过度表达促进了前列腺癌细胞的生长和转化。有趣的是，生理水平的雄激素或其他AR激动剂的存在抑制了这些效应。这些观察结果与免疫组织化学显示的人前列腺癌标本中AR和β-连环蛋白的核共定位是一致的。此外，染色质免疫沉淀分析表明，WNT3a可以将AR募集到Myc和Cyclin D1的启动子区域，这两个区域是Wnt信号通路的下游靶标。同样的分析表明，在Wnt信号转导时，AR和β-catenin可以被招募到已知AR靶基因pSA的启动子和增强子区域。这些结果表明，AR在染色质水平上促进了Wnt信号的传递。我们的发现表明，通过Wnt/β-Catenin通路的AR信号应该被添加到两条通路之间业已建立的功能相互作用中。此外，我们的数据表明，通过这种相互作用，AR可以以一种不依赖于配体的方式促进前列腺癌的发生。
A crucial event in Prostate Cancer progression is the conversion from a hormone-sensitive to a hormone-refractory disease state. Correlating with this transition, androgen receptor (AR) amplification and mutations are often observed in patients failing hormonal ablation therapies. β-Catenin, an essential component of the canonical Wnt signaling pathway, was shown to be a coactivator of the AR signaling in the presence of androgens. However, it is not yet clear what effect the increased levels of the AR could have on the Wnt signaling pathway in these hormone-refractory prostate cells. Transient transfections of several human prostate cancer cell lines with the AR and multiple components of the Wnt signaling pathway demonstrate that the AR overexpression can potentiate the transcriptional activities of Wnt/β-Catenin signaling. In addition, the simultaneous activation of the Wnt signaling pathway and overexpression of the AR promote prostate cancer cell growth and transformation at castration levels of androgens. Interestingly, the presence of physiological levels of androgen or other AR agonists inhibits these effects. These observations are consistent with the nuclear co-localization of the AR and β-Catenin shown by immunohistochemistry in human prostate cancer samples. Furthermore, chromatin immunoprecipitation assays showed that Wnt3A can recruit the AR to the promoter regions of Myc and Cyclin D1, which are well-characterized downstream targets of the Wnt signalling pathway. The same assays demonstrated that the AR and β-Catenin can be recruited to the promoter and enhancer regions of a known AR target gene PSA upon Wnt signaling. These results suggest that the AR is promoting Wnt signaling at the chromatin level. Our findings suggest that the AR signaling through the Wnt/β-Catenin pathway should be added to the well established functional interactions between both pathways. Moreover, our data show that via this interaction the AR could promote prostate cell malignancy in a ligand-independent manner.
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