The CXCL12/CXCR4 axis promotes ligand-independent activation of the androgen receptor
The CXCL12/CXCR4 axis promotes ligand-independent activation of the androgen receptor
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DOI：
10.1016/j.mce.2011.12.015
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发表时间：
2012-04-04
影响因子：
4.1
通讯作者：
Macoska, Jill A.
中科院分区：
文献类型：
--
作者：
Kasina, Sathish;Macoska, Jill A.
一些前列腺癌从雄激素配体依赖性转变为雄激素配体非依赖性的分子机制尚未完全确定。作为G蛋白偶联受体（GPCR）的配体的分子已经涉及配体非依赖性雄激素受体（AR）活化。本研究的目的是检查CXCL 12，GPCR的配体，CXCR 4，是否可能介导前列腺癌细胞增殖，通过AR依赖性机制，涉及在雄激素的情况下AR的功能性反式激活。这些研究的结果表明，CXCL 12/CXCR 4轴的激活促进：在几种前列腺上皮细胞系中野生型和突变型AR的核积累：AR依赖性增殖反应; AR辅助调节剂SRC-1蛋白的核积累; SRC-1：AR蛋白：蛋白缔合; AR和SRC-1在AR调节基因启动子上的共定位; AR调节基因的AR和SRC-1依赖性转录; AR调节PSA蛋白的AR依赖性分泌; AR的P13 K依赖性磷酸化; SRC-1的MAPK依赖性磷酸化，以及在不存在雄激素的情况下PSA蛋白的MAPK和P13 K依赖性分泌。总之，这些研究确定CXCL 12作为一种新的，非甾体生长因子，促进前列腺上皮细胞的生长，通过AR依赖的机制，在类固醇激素的情况下。这些发现支持开发靶向CXCL 12/CXCR 4轴的新型治疗剂作为靶向雄激素/AR轴的辅助治疗剂，以有效治疗去势抵抗性/复发性前列腺肿瘤。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
The molecular mechanisms responsible for the transition of some prostate cancers from androgen ligand-dependent to androgen ligand-independent are incompletely established. Molecules that are ligands for G protein coupled receptors (GPCRs) have been implicated in ligand-independent androgen receptor (AR) activation. The purpose of this study was to examine whether CXCL12, the ligand for the GPCR, CXCR4, might mediate prostate cancer cell proliferation through AR-dependent mechanisms involving functional transactivation of the AR in the absence of androgen. The results of these studies showed that activation of the CXCL12/CXCR4 axis promoted: The nuclear accumulation of both wild-type and mutant AR in several prostate epithelial cell lines: AR-dependent proliferative responses; nuclear accumulation of the AR co-regulator SRC-1 protein; SRC-1:AR protein:protein association; co-localization of AR and SRC-1 on the promoters of AR-regulated genes; AR- and SRC-1 dependent transcription of AR-regulated genes; AR-dependent secretion of the AR-regulated PSA protein; P13K-dependent phosphorylation of AR; MAPK-dependent phosphorylation of SRC-1, and both MAPK- and P13K-dependent secretion of the PSA protein, in the absence of androgen. Taken together, these studies identify CXCL12 as a novel, nonsteroidal growth factor that promotes the growth of prostate epithelial cells through AR-dependent mechanisms in the absence of steroid hormones. These findings support the development of novel therapeutics targeting the CXCL12/CXCR4 axis as an ancillary to those targeting the androgen/AR axis to effectively treat castration resistant/recurrent prostate tumors. (C) 2012 Elsevier Ireland Ltd. All rights reserved.