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

• Published in: Molecular and cellular endocrinology Vol. 351; no. 2; pp. 249 - 263
• Main Authors: Kasina, Sathish, Macoska, Jill A.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 04.04.2012
• Subjects: Activation; Androgen; Androgen receptor; androgen receptors; Androstadienes - pharmacology; Butadienes - pharmacology; Cancer; castration; Cell Line, Tumor; Cell Proliferation; chemokine CXCL12; Chemokine CXCL12 - metabolism; CXCL12; CXCR4; CXCR4 receptor; epithelial cells; Epithelial Cells - cytology; Epithelial Cells - metabolism; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Genes; Humans; Ligands; Male; mitogen-activated protein kinase; mutants; Nitriles - pharmacology; Nuclear Receptor Coactivator 1 - genetics; Nuclear Receptor Coactivator 1 - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; phosphorylation; Proliferation; Promoter Regions, Genetic; Prostate; Prostate - cytology; Prostate - metabolism; Prostate-Specific Antigen - metabolism; prostatic neoplasms; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Receptors; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Receptors, CXCR4 - metabolism; RNA Interference; RNA, Small Interfering; secretion; Secretions; steroid hormones; Transcriptional Activation; CXCR4; CXCL12; Proliferation; Androgen; Prostate; Androgen receptor
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2011.12.015

► The CXCL12/CXCR4 axis functionally activates the AR in the absence of androgen. ► CXCL12/CXCR4 promotes nuclear accumulation of the AR and SRC-1 co-regulator. ► CXCL12/CXCR4 stimulates AR-regulated gene transcription and cellular proliferation. ► CXCL12/CXCR4 activates AR and SRC-1 viaPI3K- and MAPK-mediated phosphorylation. ► CXCL12/CXCR4-mediated AR activation may provide a new therapeutic target. 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, non-steroidal 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.