Mechanisms by which interleukin-6 regulates prostate-specific antigen gene expression in prostate LNCaP carcinoma cells.
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.
Department of Urology, Chang Gung University, 259 Wen-Hua 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan, Republic of China.
Ke-Hung
KH
Tsui
Yu-Fen
YF
Lin
Yu-His
YH
Chen
Phei-Lang
PL
Chang
Horng-Heng
HH
Juang
D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D017430:Prostate-Specific Antigen / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D047029:Lactams, Macrocyclic; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; C076035:c-MYC-associated zinc finger protein; C112765:tanespimycin; D017430:Prostate-Specific Antigen; C001277:geldanamycin