323 ANALYSIS OF UP-REGULATED CYP17A1 EXPRESSION UNDER ANTI-ANDROGEN STRATEGIES IN CASTRATION RESISTANT PROSTATE CANCER (2013)

You have accessJournal of UrologyProstate Cancer: Basic Research (II)1 Apr 2013323 ANALYSIS OF UP-REGULATED CYP17A1 EXPRESSION UNDER ANTI-ANDROGEN STRATEGIES IN CASTRATION RESISTANT PROSTATE CANCER Elmar Heinrich, Lutz Tojan, Felix Bremmer, Arne Strauss, and Paul Thelen Elmar HeinrichElmar Heinrich Goettingen, Germany More articles by this author , Lutz TojanLutz Tojan Goettingen, Germany More articles by this author , Felix BremmerFelix Bremmer Goettingen, Germany More articles by this author , Arne StraussArne Strauss Goettingen, Germany More articles by this author , and Paul ThelenPaul Thelen Goettingen, Germany More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1708AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clinically efficient therapies targeting androgen receptor (AR) signalling in CRPC either obviate AR activation by multifunctional receptor blockade or by elimination of androgen synthesis. Enduring effectiveness of anti-androgen therapies may be limited due to resistance mechanisms occurring under treatment such as CYP17A1 up-regulation when abiraterone acetate is used. In this study we investigate alterations of CYP17A1 expression according to anti-androgen strategies in CRPC cell models. METHODS CRPC cell models VCaP and LNCaP comprising AR overexpression or AR mutation, respectively, as well as AR-negative PC-3 and non-neoplastic epithelial BPH-1-cells were treated with various concentrations (5 to 25 μmol/L) of abiraterone acetate (AA, Janssen-Cilag, Germany). Functional analyses by RNA interference were performed with AR- and CYP17A1-siRNA. Expression of androgen regulated genes and CYP17A1, AKR1C3 was quantitated by real time PCR, western blots and ELISA tests. RESULTS AA treatments of AR positive CRPC cell models led to decreased expression of androgen regulated genes. Expression alterations of androgen regulated genes were accompanied by an up-regulation of CYP17A1 expression (>2-fold at 25μmol/L AA) within short treatments of 24 hours. No such effects were seen in AR-negative PC-3 cells. siRNA targeting AR (siAR) used in VCaP cells significantly reduced mRNA expression and AR protein as compared with control transfections. Even though AA was absent in these experiments such interference with AR signalling caused an up-regulation (8-fold) of CYP17A1 expression. CONCLUSIONS In AR-positive cells AA treatments caused a down-regulation of androgen regulated genes although an elevated expression of the AA target enzyme CYP17A1 became measurable. CYP17A1 up-regulation in AR positive cells already occurs within 24 hour AA treatments and does not require adaptation events over several cell cycles. CYP17A1 is also up-regulated in the absence of AA when AR expression is eliminated by siAR. Obviously, an immediate feedback regulation of CYP17A1 expression commences when AR-signalling is inhibited not necessarily eliciting drug resistance. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e131 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Elmar Heinrich Goettingen, Germany More articles by this author Lutz Tojan Goettingen, Germany More articles by this author Felix Bremmer Goettingen, Germany More articles by this author Arne Strauss Goettingen, Germany More articles by this author Paul Thelen Goettingen, Germany More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...