MP29-08 HSD3B1 PREFERENTIALLY UTILIZES PREGNENOLONE TO PROMOTE RESISTANCE TO ANTI-ANDROGENS IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I1 Apr 2018MP29-08 HSD3B1 PREFERENTIALLY UTILIZES PREGNENOLONE TO PROMOTE RESISTANCE TO ANTI-ANDROGENS IN PROSTATE CANCER Cameron Armstrong, Chengfei Liu, Wei Lou, Christopher Evans, and Allen Gao Cameron ArmstrongCameron Armstrong More articles by this author , Chengfei LiuChengfei Liu 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.2018.02.928AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Most prostate cancer (PCa) patients receiving enzalutamide (Enza) or abiraterone (Abi) develop drug resistance within 24 months of exposure. This creates a need to better understand the underlying causes of anti-androgen resistance so that improved treatment methods can be developed. Previous studies demonstrate that uncontrolled intraprostatic androgen synthesis promotes Enza and Abi resistance. HSD3B1 is a key enzyme contributing to androgen synthesis and its expression is associated with PCa progression. The aim of this study is to determine the contribution of HSD3B1 to Enza and Abi resistance in PCa. METHODS Enza resistant (C4-2B MDVR) and Abi resistant (C4-2B AbiR) C4-2B PCa cells were generated by chronically exposing parental C4-2B cells to increasing Enza or Abi concentrations for >12 months and maintained in 20 μM Enza or 10 μM Abi. Differences in gene expression between parental and anti-androgen resistant cells was determined by microarray, RNA-seq, and rtPCR. HSD3B1 expression was knocked down in C4-2B MDVR and C4-2B AbiR cells using shRNA and cell number was determined in media containing FBS, charcoal dextran stripped FBS (CD-FBS), or CD-FBS supplemented with 100 nM pregnenolone (P5), 100 nM DHEA, or 10 nM DHT in the presence and absence of 20 μM Enza. PSA secretion was determined by ELISA and PSA-luciferase activity was measured by reporter assay. RESULTS HSD3B1 expression is higher in C4-2B MDVR and C4-2B AbiR cells compared to parental C4-2B cells. This correlates to increased intracrine androgens in C4-2B MDVR cells. Knockdown of HSD3B1 in C4-2B MDVR resensitized cells to Enza in FBS, CD-FBS+DHT and CD-FBS+P5 conditions as determined by a reduction in cell number and PSA secretion and/or PSA-luciferase activity in response to Enza. In the C4-2B AbiR cells, inhibition of HSD3B1 re-sensitized cells to treatment with Abi in FBS, CD-FBS, and CD-FBS + P5 conditions with the greatest effects seen in the FBS and CD-FBS + P5 containing media. Supplementation with P5, but not DHEA, was able to induce PSA-luciferase activity and cell growth in C4-2B AbiR cells and this could be blocked by knockdown of HSD3B1. CONCLUSIONS HSD3B1 overexpression in C4-2B MDVR and C4-2B AbiR cells contributes to Enza and Abi resistance and modulation of this enzyme could be a viable strategy to improve anti-androgen response in PCa cells. HSD3B1 activity appears to be reliant on select androgen precursors, such as pregnenolone, indicating preference towards a specific androgen synthesis pathway by HSD3B1 in mediating anti-androgen resistance. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e368-e369 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Cameron Armstrong More articles by this author Chengfei Liu 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 ...