1291 INTERLEUKIN-6 REGULATES INTRACRINE ANDROGEN SYNTHESIS IN PROSTATE CANCER CELLS (2010)

You have accessJournal of UrologyProstate Cancer: Basic Research VII1 Apr 20101291 INTERLEUKIN-6 REGULATES INTRACRINE ANDROGEN SYNTHESIS IN PROSTATE CANCER CELLS Jae Chun, Nagalskshmi Nadiminty, Wei Lou, Christopher Evans, and Allen Gao Jae ChunJae Chun More articles by this author , Nagalskshmi NadimintyNagalskshmi Nadiminty More articles by this author , Wei LouWei Lou More articles by this author , Christopher EvansChristopher Evans More articles by this author , and Allen GaoAllen Gao More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.875AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although serum testosterone concentrations were significantly reduced after androgen deprivation therapy, levels of intraprostatic androgens are reproducibly measured at concentrations sufficient to activate androgen receptor (AR) and stimulate tumor growth, suggesting that prostate cancer cells may survive androgen deprivation therapies by increasing intracrine androgen synthesis within the prostate. However, factors that regulate de novo intracrine androgen synthesis have not been identified. Interleukin-6 (IL-6) has been implicated in the modulation of AR activation and growth and differentiation in prostate cancer. In this study, we investigate whether IL-6 regulates intraprostatic androgen synthesis in prostate cancer cells. METHODS Quantitative reverse transcription-PCR and western blot were performed 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 siRNAs specific to IL-6R and gp130 and the effect on AKR1C3 expression was examined. To measure intraprostatic androgen levels, IL-6 overexpressing LNCaP-IL6+ cells were inoculated orthotopically into the prostate of castrated male nude mice and generated tumors. Intraprostatic androgen levels were measured by an enzyme immunoassay (Testosterone EIA kit) based on the competition between testosterone and a testosterone-acetylcholinesterase (AChE) conjugate (testosterone tracer) for a limited amount of testosterone in the sample. 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 siRNA 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 during androgen deprivation therapy. Sacramento, CA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e499-e500 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jae Chun More articles by this author Nagalskshmi Nadiminty More articles by this author Wei Lou More articles by this author Christopher Evans More articles by this author Allen Gao More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...