237 β-TRCP INHIBITION REDUCES PROSTATE CANCER CELL GROWTH VIA UPREGULATION OF THE ARYL HYDROCARBON RECEPTOR

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2010237 β-TRCP INHIBITION REDUCES PROSTATE CANCER CELL GROWTH VIA UPREGULATION OF THE ARYL HYDROCARBON RECEPTOR Udi Gluschnaider, Guy Hidas, Gady Cojucaru, Vladimir Yutkin, Dov Pode, Yinon Ben-Neriah, and Eli Pikarsky Udi GluschnaiderUdi Gluschnaider More articles by this author , Guy HidasGuy Hidas More articles by this author , Gady CojucaruGady Cojucaru More articles by this author , Vladimir YutkinVladimir Yutkin More articles by this author , Dov PodeDov Pode More articles by this author , Yinon Ben-NeriahYinon Ben-Neriah More articles by this author , and Eli PikarskyEli Pikarsky More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.295AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Beta-transducin repeats-containing proteins (βTrCP) is an E3 ubiquitin ligase that targets various substrates essential for many aspects of tumorigenesis. One important β-TrCP substrate -catenin) was shown to regulate transcription of the aryl hydrocarbon (dioxin) receptor (AhR) in prostate cancer cells. AhR is a ligand activated transcription factor involved in organogenesis, cellular detoxification and malignant transformation. Recent studies showed connection between the AhR pathway and prostate cancer. This research aims to explore the consequences of β-TrCP inhibition and the role of the AhR pathway in prostate cancer. METHODS We used shRNA targeted both against β-TrCP and AhR. Charcoal stripped serum was administrated to cell cultures, in order to mimic the hormonal treatment. We monitored culture cell growth utilizing the XTT method. NUDE mice bearing human prostate cancer xenografts, were used for in vivo studies. To evaluate AhR status in patients, we conducted immunohistochemistry analyses. RESULTS We show that β-TrCP depletion suppresses prostate cancer growth and identify a specific growth control mechanism. Both shRNA targeted against β-TrCP and over expression of a dominant negative form of β-TrCP, reduced prostate cancer cell growth and cooperated with androgen ablation in vitro and in vivo. We found that β-TrCP inhibition leads to upregulation of the AhR. shRNA mediated of the AhR proved that its upregulation was the principal mediator of this therapeutic effect. This phenomenon is presumably ligand independent, as addition of the AhR ligand 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) did not alter prostate cancer cell growth. We detected high AhR expression and activation in basal cells and atrophic epithelial cells of human cancer bearing prostates. AhR expression and activation is also significantly higher in prostate cancer cells compared to the benign glandular epithelium. CONCLUSIONS Together these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining β-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients. Jerusalem, Israel© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e92-e93 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Udi Gluschnaider More articles by this author Guy Hidas More articles by this author Gady Cojucaru More articles by this author Vladimir Yutkin More articles by this author Dov Pode More articles by this author Yinon Ben-Neriah More articles by this author Eli Pikarsky More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...