Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth
Inhibition of glycogen synthase kinase-3 represses androgen receptor activity and prostate cancer cell growth
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DOI：
10.1038/sj.onc.1208068
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发表时间：
2004-10-14
期刊：
影响因子：
8
通讯作者：
Kypta, RM
中科院分区：
文献类型：
--
作者：
Mazor, M;Kawano, Y;Kypta, RM
雄激素受体（AR）的转录活性通过与各种共调节因子的相互作用来调节，其中之一是β-连环蛋白。对β-连环蛋白在前列腺癌中的作用的兴趣已经被以下报道所激发，所述报道显示其在高达38%的前列腺癌难治性肿瘤的细胞质和/或细胞核中异常表达，并且β-连环蛋白的过表达导致AR转录活性的激活。我们已经使用Axin和RNA干扰检测了内源性β-连环蛋白耗竭对AR活性的影响。促进β-连环蛋白降解的Axin抑制AR转录活性。然而，这并不需要Axin的β-连环蛋白结合结构域。使用RNA干扰去除β-连环蛋白增加而不是降低AR活性，表明内源性β-连环蛋白不是AR的转录共激活因子。Axin的糖原合成酶激酶-3（GSK-3）结合结构域阻止GSK-3-AR复合物的形成，并且对于抑制AR依赖性转录是必要且充分的。第二种GSK-3结合蛋白FRAT也抑制AR转录活性，GSK-3抑制剂SB 216763和SB 415286也是如此。最后，GSK-3的抑制降低了AR表达前列腺癌细胞系的生长。我们的观察表明GSK-3抑制剂在前列腺癌中的潜在新治疗应用。
The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which is beta-catenin., Interest in the role of beta-catenin in prostate cancer has been stimulated by reports showing that it is aberrantly expressed in the cytoplasm and/or nucleus in up to 38% of hormone-refractory tumours and that overexpression of beta-catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenous beta-catenin on AR activity using Axin and RNA interference. Axin, which promotes beta-catenin degradation, inhibited AR transcriptional activity. However, this did not require the beta-catenin-binding domain of Axin. Depletion of beta-catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenous beta-catenin is not a transcriptional coactivator for the AR. The glycogen synthase kinase-3 (GSK-3)-binding domain of Axin prevented formation of a GSK-3-AR complex and was both necessary and sufficient for inhibition of AR-dependent transcription. A second GSK-3-binding protein, FRAT, also inhibited AR transcriptional activity, as did the GSK-3 inhibitors SB216763 and SB415286. Finally, inhibition of GSK-3 reduced the growth of AR-expressing prostate cancer cell lines. Our observations suggest a potential new therapeutic application for GSK-3 inhibitors in prostate cancer.