Androgen receptor signaling: mechanism of interleukin-6 inhibition.
Nonsteroidal signaling via the androgen receptor (AR) plays an im-portant role in hormone-refractory prostate cancer. Previously, we have reported that the pleiotropic cytokine, interleukin (IL)-6, inhibited dihydrotestosterone-mediated expression of prostate-specific antigen in LNCaP cells (Jia et al., Mol Can Res 2003;1:385-92). In the present study, we explored the mechanisms involved in this inhibition and considered possible effects on AR nuclear translocation, recruitment of transcription cofactors, and the signaling pathways that may mediate this inhibitory effect. IL-6 neither induced nuclear localization of the AR nor inhibited dihydrotestosterone-induced nuclear translocation of the receptor. IL-6 did not affect AR or p160 coactivator recruitment to the transcription initiation complex on the prostate-specific antigen enhancer and promoter. Moreover, it did not lead to the recruitment of the corepressor silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) or histone deacetylase 1 (HDAC1) at the same sites. IL-6 did, however, prevent the recruitment of the secondary coactivator, p300, to the complex and partially inhibited histone H3 acetylation at the same loci. Furthermore, inhibition by IL-6 was not mediated by the mitogen-activated protein kinase or the Akt pathways and was partially abrogated by signal transducers and activators of transcription-3 knock-down using small interfering RNA. Our results show that IL-6 modulates androgen action through the differential recruitment of cofactors to target genes. These findings may account for the pleiotropic actions of IL-6 in malignant prostate cells.
Jia
Li
L
Department of Urology and Preventive Medicine, Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90089, USA.
Choong
Catherine S-Y
CS
Ricciardelli
Carmela
C
Kim
Joshua
J
Tilley
Wayne D
WD
Coetzee
Gerhard A
GA
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013196:Dihydrotestosterone / Q000037:antagonists & inhibitors; D015870:Gene Expression / Q000187:drug effects; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D015850:Interleukin-6; C539130:NCOR2 protein, human; D009687:Nuclear Proteins; D056985:Nuclear Receptor Co-Repressor 2; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D013196:Dihydrotestosterone; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017430:Prostate-Specific Antigen; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases