The transcriptional co-activator cAMP response element-binding protein-binding protein is expressed in prostate cancer and enhances androgen- and anti-androgen-induced androgen receptor function
The transcriptional co-activator cAMP response element-binding protein-binding protein is expressed in prostate cancer and enhances androgen- and anti-androgen-induced androgen receptor function
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DOI：
10.1016/s0002-9440(10)63814-x
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发表时间：
2003-01-01
影响因子：
6
通讯作者：
Culig, Z
中科院分区：
文献类型：
--
作者：
Comuzzi, B;Lambrinidis, L;Culig, Z
在存在野生型或突变雄激素受体（AR）的情况下，人类前列腺癌向治疗耐药性的进展发生，在某些情况下，这些受体表现出各种类固醇激素和抗雄激素的异常激活。AR与许多具有组蛋白乙酰化酶活性的共激活剂结合，并作为转录起始复合物组分的桥接分子。在先前的报道中，显示转录共激活因子CREB（cAMP应答元件结合蛋白）结合蛋白（CBP）以配体依赖性方式增强AR活性。在本研究中，我们研究了CBP是否改变了非甾体抗雄激素羟氟沙星和比卡鲁胺的拮抗剂/激动剂平衡。在用CBP cDNA瞬时转染的前列腺癌DU-145细胞中，在存在野生型或突变AR 730瓦尔-->met的情况下，羟基芴醇增强AR活性的程度大于比卡鲁胺。在含有突变的AR 877 thr->ala和过表达CBP的LNCaP细胞的两个亚系中，用羟基芴醇处理后观察到AR活性增加，但用比卡鲁胺处理后未观察到AR活性增加。抗雄激素并没有影响AR的表达与CBP cDNA转染的细胞，通过Western印迹分析判断。内源性CBP蛋白通过蛋白质印迹法在来自三种前列腺癌细胞系LNCaP、PC-3和DU-145的核提取物中检测到，所述细胞系均来自治疗抗性前列腺癌。此外，CBP在良性前列腺上皮、高级别前列腺上皮内瘤变和前列腺癌临床标本的基底细胞和分泌细胞中均表达，如免疫组织化学染色所证明。综上所述，我们的研究结果表明，转录共激活因子CBP选择性增强了抗雄激素羟氟沙星的激动作用，这是一种新的，潜在的相关机制，有助于获得前列腺癌的治疗耐药性。
Progression of human prostate cancer toward therapy resistance occurs in the presence of wild-type or mutated androgen receptors (ARs) that, in some cases, exhibit aberrant activation by various steroid hormones and anti-androgens. The AR associates with a number of co-activators that possess histone acetylase activity and act as bridging molecules to components of the transcription initiation complex. in previous reports, it was shown that the transcriptional co-activator CREB (cAMP response element-binding protein)-binding protein (CBP) enhances AR activity in a ligand-dependent manner. In the present study, we have investigated whether CBP modifies antagonist/agonist balance of the nonsteroidal anti-androgens hydroxyflutamide and bicalutamide. In prostate cancer DU-145 cells, which were transiently transfected with CBP cDNA, hydroxyflutamide enhanced AR activity to a greater extent than bicalutamide in the presence of either wild-type or the mutated AR 730 val-->met. In two sublines of LNCaP cells that contain the mutated AR 877 thr-->ala and overexpressed CBP, Increase in AR activity was observed after treatment with hydroxyflutamide but not with bicalutamide. Anti-androgens did not influence AR expression in cells transfected with CBP cDNA, as judged by Western blot analysis. Endogenous CBP protein was detected by Western blot in nuclear extracts from the three prostate cancer cell lines, LNCaP, PC-3, and DU-145, all derived from therapy-resistant prostate cancer. in addition, CBP was ex pressed in both basal and secretory cells of benign prostate epithelium, high-grade prostate intraepithelial neoplasia, and prostate cancer clinical specimens, as evidenced by immunohistochemical staining. Taken together, our findings demonstrate the selective enhancement of agonistic action of the anti-androgen hydroxyflutamide by the transcriptional co-activator CBP, which is a new, potentially relevant mechanism contributing to the acquisition of therapy resistance in prostate cancer.