RRC ID 11935
Author Tsui KH, Lin YF, Chen YH, Chang PL, Juang HH.
Title Mechanisms by which interleukin-6 regulates prostate-specific antigen gene expression in prostate LNCaP carcinoma cells.
Journal J Androl
Abstract Interleukin-6 (IL-6) is involved in regulation of cell growth and survival of prostate carcinoma cells. Previous studies suggest that IL-6 promotes prostate cancer progression through the induction of an androgen-independent response. In this study, we evaluated the mechanisms by which IL-6 regulates the gene expression of prostate-specific antigen (PSA) in human prostate LNCaP carcinoma cells. (3)H-thymidine incorporation assays revealed that IL-6 treatment inhibited the proliferation of LNCaP cells. Results of enzyme-linked immunosorbent assay (ELISA) and immunoblot assays indicated that IL-6 treatment enhanced PSA gene expression. Similar results were found in LNCaP cells that had been engineered to stably overexpress IL-6. Although forced overexpression of c-Myc-associated zinc finger protein (MAZ) induced PSA promoter activity, mutation of the MAZ response elements had little effect on IL-6-induced PSA promoter activity. Results from 5'-deletion reporter assays revealed that the effects of IL-6 appear to be mediated via an androgen enhancer region (24801 to 23933), which is dependent on the signal transducer and activator of the transcription 3 (STAT3) pathway, and a region located at 2193 to 241 base pairs upstream of the translational initiation site of the human PSA gene, which did not respond to androgen or STAT3. Results of reporter assays, immunoblot assays, and ELISA revealed that the heat shock protein 90 (Hsp90) inhibitors 17-allyamino-17-demethoxygeldanamycin and geldanamycin blocked IL-6-induced PSA gene expression. Those results suggest that IL-6 upregulates PSA gene expression and that Hsp90 plays a novel role in the activation of IL-6 on PSA gene expression in an androgen-independent manner.
Volume 32(4)
Pages 383-93
Published 2011-1-1
DOI 10.2164/jandrol.109.009878
PII jandrol.109.009878
PMID 21051589
MeSH Benzoquinones / pharmacology Cell Line, Tumor DNA-Binding Proteins / metabolism Gene Expression Regulation, Neoplastic / drug effects HSP90 Heat-Shock Proteins / antagonists & inhibitors Humans Interleukin-6 / physiology* Lactams, Macrocyclic / pharmacology Male Prostate-Specific Antigen / biosynthesis* Prostatic Neoplasms / genetics* Prostatic Neoplasms / pathology STAT3 Transcription Factor / physiology Transcription Factors / metabolism
Times Cited 13
DNA material pCMV-MAZ pCMV-MAZi (RDB03219)