IL6 and Prostate Cancer
EXPERIMENTAL DESIGN: Quantitative reverse transcription-PCR and Western blotting were done to detect expression levels of steroidogenic enzymes. AKR1C3 promoter reporter was constructed and analyzed for IL-6-mediated AKR1C3 transcriptional activity. IL-6-mediated signaling was knocked down using small interfering RNA specific to IL-6 receptor and gp130, and the effect on AKR1C3 expression was examined. Intraprostatic androgen levels in prostate cancer cells in culture and in tumors were measured by an enzyme immunoassay (Testosterone EIA kit).
RESULTS: We found that IL-6 increases the expression of genes encoding many steroidogenic enzymes, including HSD3B2 and AKR1C3, involved in androgen biosynthesis. Down-regulation of IL-6 receptor and gp130 expression using specific small interfering RNA abolished IL-6-mediated AKR1C3 expression, suggesting that IL-6 signaling is responsible for AKR1C3 expression. IL-6 increases AKR1C3 promoter activity, indicating that the increase in IL-6-mediated AKR1C3 expression is in part at the transcriptional level. Treatment of IL-6 increased testosterone level in LNCaP cells. The tumor testosterone levels were detected at 378 pg/g in tumors generated from IL-6-overexpressing LNCaP-IL6(+) cells inoculated orthotopically into the prostates of castrated male nude mice.
CONCLUSIONS: These results suggest that IL-6 increases levels of intracrine androgens through enhanced expression of genes mediating androgen metabolism in prostate cancer cells.
Chun JY, Nadiminty N, Dutt S, Lou W, Yang JC, Kung HJ, Evans CP, Gao AC.
Interleukin-6 regulates androgen synthesis in prostate cancer cells.
Clin Cancer Res.
Department of Urology, Graduate Program of Pharmacology and Toxicology, and Department of Biological Chemistry, and Cancer Center, University of California at Davis, Sacramento, CA 95817, USA.