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https://hdl.handle.net/2440/9352
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Type: | Journal article |
Title: | Androgen receptor signaling: mechanism of interleukin-6 inhibition |
Author: | Jia, L. Choong, C. Ricciardelli, C. Kim, J. Tilley, W. Coetzee, G. |
Citation: | Cancer Research, 2004; 64(7):2619-2626 |
Publisher: | Amer Assoc Cancer Research |
Issue Date: | 2004 |
ISSN: | 0008-5472 1538-7445 |
Statement of Responsibility: | Li Jia, Catherine S-Y. Choong, Carmela Ricciardelli, Joshua Kim, Wayne D. Tilley, and Gerhard A Coetzee |
Abstract: | Nonsteroidal signaling via the androgen receptor (AR) plays an important 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. |
Keywords: | Cell Line, Tumor Cell Nucleus Humans Prostatic Neoplasms Dihydrotestosterone Histone Deacetylases Prostate-Specific Antigen DNA-Binding Proteins Trans-Activators Proto-Oncogene Proteins Nuclear Proteins Receptors, Androgen Repressor Proteins Interleukin-6 Signal Transduction Gene Expression Male STAT3 Transcription Factor Proto-Oncogene Proteins c-akt Transcriptional Activation Histone Deacetylase 1 Nuclear Receptor Co-Repressor 2 Protein Serine-Threonine Kinases |
Description: | © 2004 American Association for Cancer Research |
DOI: | 10.1158/0008-5472.CAN-03-3486 |
Published version: | http://cancerres.aacrjournals.org/cgi/content/abstract/64/7/2619 |
Appears in Collections: | Aurora harvest Medicine publications Obstetrics and Gynaecology publications |
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