Alien interacts with the human androgen receptor and inhibits prostate cancer cell growth
Alien interacts with the human androgen receptor and inhibits prostate cancer cell growth
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DOI：
10.1210/me.2006-0468
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发表时间：
2007-05-01
影响因子：
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通讯作者：
Baniahmad, Aria
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文献类型：
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作者：
Moehren, Udo;Papaioannou, Maria;Baniahmad, Aria
前列腺癌细胞的生长最初依赖于雄激素。雄激素拮抗剂用于前列腺癌治疗，以使人雄激素受体（hAR）的转录活性失活并抑制前列腺癌的增殖。在这里，我们将Alien与一种辅抑制因子的特征进行了表征，作为拮抗剂结合hAR的一种新的相互作用因子。在AR拮抗剂醋酸环丙孕酮（CPA）存在的情况下，Alien被招募到hAR。通过改进的哺乳动物双杂交系统、共免疫沉淀、染色质免疫沉淀和体外结合试验，在体内和体外验证了Alien与hAR的相互作用。与其他核受体不同，Alien与hAR的氨基末端结合，参与了受体SUMOylation（小泛素修饰因子）位点。此外，在用CPA治疗前列腺癌细胞后，Alien的细胞定位转变为主要的核定位。值得注意的是，在CPA存在的情况下，Alien在LNCaP细胞中的稳定表达抑制了内源性前列腺特异性抗原的表达和这些细胞的增殖，而在AR激动剂存在的情况下则没有。这些发现强调了辅抑制因子对雄激素拮抗剂抑制前列腺癌细胞生长的重要性。
Prostate cancer cell growth is initially androgen dependent. Androgen antagonists are used in prostate cancer therapy to inactivate the transcriptional activity of the human androgen receptor (hAR) and to inhibit the proliferation of prostate cancer. Here, we have characterized Alien with characteristics of a corepressor as a novel interacting factor for the antagonist bound hAR. Alien is recruited to hAR in the presence of the AR antagonist cyproterone acetate (CPA). The interaction of Alien with hAR is verified in vivo and in vitro by a modified mammalian two-hybrid system, coimmunoprecipitation, chromatin immunoprecipitation, and in vitro binding assays. In contrast to other nuclear receptors, Alien binds to the amino-terminus of hAR with the receptor SUMOylation ( small ubiquitin modifier) sites being involved. Furthermore, cellular localization of Alien is changed towards a predominant nuclear localization upon treatment of prostate cancer cells with CPA. Notably, stable expression of Alien in LNCaP cells inhibits both endogenous prostate-specific antigen expression and proliferation of these cells in the presence of CPA but not in the presence of an AR agonist. These findings underline the importance of corepressors for inhibition of prostate cancer cell growth by androgen antagonists.