The CXCL12/CXCR4 axis promotes ligand-independent activation of the androgen receptor

被引:38
作者
Kasina, Sathish [1 ]
Macoska, Jill A. [1 ,2 ]
机构
[1] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA
基金
美国国家卫生研究院;
关键词
CXCL12; CXCR4; Androgen; Androgen receptor; Prostate; Proliferation; PROSTATE-CANCER CELLS; SIGNAL-TRANSDUCTION PATHWAYS; EPIDERMAL-GROWTH-FACTOR; AMINO-TERMINAL DOMAIN; FACTOR-I; EXPRESSION; COACTIVATOR; PHOSPHORYLATION; PROLIFERATION; LNCAP;
D O I
10.1016/j.mce.2011.12.015
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:249 / 263
页数:15
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