title: The CXCL12/CXCR4 axis promotes ligand-independent activation of the androgen receptor.
abstract: 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.
authors.affiliation: Department of Urology, The University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sathish
authors.initials: S
authors.lastname: Kasina
authors.forename: Jill A
authors.initials: JA
authors.lastname: Macoska
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000166:cytology* / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015533:Transcriptional Activation; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002070:Butadienes; D054377:Chemokine CXCL12; D048049:Extracellular Signal-Regulated MAP Kinases; D008024:Ligands; D009570:Nitriles; D056920:Nuclear Receptor Coactivator 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017430:Prostate-Specific Antigen; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D019718:Receptors, CXCR4; D000077191:Wortmannin; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C113580:U 0126