MP46-05 INHIBITION OF CONSTITUTIVELY ACTIVE STAT3 AND AR VARIANTS REVERSES ENZALUTAMIDE RESISTANCE IN ADVANCED PROSTATE CANCER CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2015MP46-05 INHIBITION OF CONSTITUTIVELY ACTIVE STAT3 AND AR VARIANTS REVERSES ENZALUTAMIDE RESISTANCE IN ADVANCED PROSTATE CANCER CELLS Chengfei Liu, Wei Lou, Yezi Zhu, Christopher Evans, and Allen Gao Chengfei LiuChengfei Liu More articles by this author , Wei LouWei Lou More articles by this author , Yezi ZhuYezi Zhu 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.2015.02.1568AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Use of enzalutamide has improved treatment of advanced prostate cancer. However, development of resistance to enzalutamide frequently occurs. This study aimed to test whether overexpression of IL-6 and constitutive activation of AR variants in prostate cancer cells increase resistance to enzalutamide and identify inhibitors of AR variants and test its ability to overcome resistance to enzalutamide. METHODS Sensitivity of prostate cancer cells to enzalutamide was tested using cell growth assays and clonogenic assays. Expression of Stat3 and AR-V7 was downregulated using siRNA specific to Stat3 and AR-V7. Drug screening was conducted using luciferase activity assay to determine the activity of AR-V7 after treatment with the compounds in the Prestwick Chemical Library, which contains about 1120 FDA-approved drugs. The effects of the identified inhibitors on AR-V7 activity and enzalutamide sensitivity were characterized in CRPC and enzalutamide-resistant prostate cancer cells in vitro and in vivo. RESULTS Prostate cancer cells expressing autocrine IL-6 are resistant to enzalutamide through constitutive activation of Stat3 and its target genes. Down regulation of Stat3 and AR variants led to an increase in sensitivity of prostate cancer cells to enzalutamide. Prostate cancer cells chronically treated with enzalutamide express AR variants. Niclosamide, an FDA-approved anti-helminthic drug, was identified as a potent AR-V7 inhibitor in prostate cancer cells. Niclosamide significantly downregulated AR-V7 protein expression by protein degradation through a proteasome dependent pathway. Niclosamide also inhibited AR-V7 transcription activity and reduced the recruitment of AR-V7 to the PSA promoter. Niclosamide inhibited prostate cancer cell growth in vitro and tumor growth in vivo. Furthermore, the combination of niclosamide and enzalutamide resulted in significantly inhibition of enzalutamide-resistant tumor growth, suggesting that Niclosamide enhances enzalutamide therapy and overcomes enzalutamide resistance in castration resistant prostate cancer cells. CONCLUSIONS Activation of IL6-Stat3-AR axis confers resistance to enzalutamide. Niclosamide was identified as a novel inhibitor of AR variants. Our findings offer preclinical validation of niclosamide as a promising inhibitor of androgen receptor variants to treat, either alone or in combination with current antiandrogen therapies, advanced prostate cancer patients, especially those resistant to enzalutamide. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e545 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Chengfei Liu More articles by this author Wei Lou More articles by this author Yezi Zhu 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 ...