Androgen axis in prostate cancer
Androgen axis in prostate cancer
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DOI：
10.1002/jcb.20898
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发表时间：
2006-10-01
影响因子：
4
通讯作者：
Bartsch, Georg
中科院分区：
文献类型：
--
作者：
Culig, Zoran;Bartsch, Georg
晚期前列腺癌的内分泌治疗是基于雄激素消融或雄激素受体（AR）阻断。AR在前列腺癌中的作用已在许多细胞系、其衍生物和转基因动物中进行了研究。AR在前列腺癌中的表达是异质性的，它可以在大多数原发肿瘤及其转移灶中检测到。然而，由于基因启动子的表观遗传变化，一些细胞缺乏AR。体外慢性雄激素消融后AR表达增加。在几种异种移植物中，AR上调是在向治疗抗性进展期间鉴定的最一致的变化。相反，AR通路可能在非甾体类抗雄激素长期治疗期间被旁路。前列腺癌中AR敏感性的增加是Ras/促分裂原活化蛋白激酶途径激活的结果。前列腺癌的内分泌治疗的主要困难之一是在突变的AR存在下观察到的AR拮抗剂的激动特性的获得。相关的辅激活蛋白增强AR功能已被广泛研究。辅助因子SRC-1、RAC 3、p300/CBP、TIF-2和Tip 60在晚期前列腺癌中上调。大多数关于AR的配体非依赖性激活的研究集中在Her-2/neu和白细胞介素-6（IL-6）上。基于显示晚期前列腺癌中AR过表达和活化的研究，表明减少AR表达的新疗法将为患者提供益处。有实验证据表明，前列腺肿瘤的生长在体外和体内的抑制后，管理的化学预防药物或反义寡核苷酸，下调AR mRNA和蛋白质的表达。J.细胞。99：373-381，2006. (c)2006 Wiley-Liss，Inc.
Endocrine therapy for advanced prostate cancer is based on androgen ablation or blockade of the androgen receptor (AR). AR action in prostate cancer has been investigated in a number of cell lines, their derivatives, and transgenic animals. AR expression is heterogenous in prostate cancer in vivo; it could be detected in most primary tumors and their metastases. However, some cells lack the AR because of epigenetic changes in the gene promoter. AR expression increases after chronic androgen ablation in vitro. In several xenografts, AR upregulation is the most consistent change identified during progression towards therapy resistance. In contrast, the AR pathway may be by-passed during chronic treatment with a nonsteroidal anti-androgen. AR sensitivity in prostate cancer increases as a result of activation of the Ras/ mitogen-activated protein kinase pathway. One of the major difficulties in endocrine therapy for prostate cancer is acquisition of agonistic properties of AR antagonists observed in the presence of mutated AR. Enhancement of AR function by associated coactivator proteins has been extensively investigated. Cofactors SRC-1, RAC3, p300/CBP, TIF-2, and Tip60 are upregulated in advanced prostate cancer. Most studies on ligand-independent activation of the AR are focused on Her-2/neu and interleukin-6 (IL-6). On the basis of studies that showed overexpression and activation of the AR in advanced prostate cancer, it was suggested that novel therapies that reduce AR expression will provide a benefit to patients. There is experimental evidence showing that prostate tumor growth in vitro and in vivo is inhibited following administration of chemopreventive drugs or antisense oligonucleotides that downregulate AR mRNA and protein expression. J. Cell. Biochem. 99: 373-381, 2006. (c) 2006 Wiley-Liss, Inc.