MP66-06 THE ROLE OF THE PKD1-β-CATENIN-ANDROGEN RECEPTOR AXIS IN PROSTATE CANCER PROGRESSION

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II1 Apr 2016MP66-06 THE ROLE OF THE PKD1-β-CATENIN-ANDROGEN RECEPTOR AXIS IN PROSTATE CANCER PROGRESSION Bita Nick Kholgh, Michael B. Rothberg, Sittadjody Sivanandane, Xiaolan Fang, and K.C. Balaji Bita Nick KholghBita Nick Kholgh More articles by this author , Michael B. RothbergMichael B. Rothberg More articles by this author , Sittadjody SivanandaneSittadjody Sivanandane More articles by this author , Xiaolan FangXiaolan Fang More articles by this author , and K.C. BalajiK.C. Balaji More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1280AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prior studies have described androgen receptor (AR) involvement in the nuclear translocation of β-catenin; in turn, β-catenin acts as coactivator of AR and enhances AR-mediated transcription. It has been shown that phosphorylation of β-catenin at the threonine 120 (T120) residue decreases active β-catenin (ABC) expression. Currently the only known upstream kinase for T120-β-catenin phosphorylation is protein kinase D1 (PKD1), a novel tumor and metastasis suppressor in prostate cancer (PCa). In progressive PCa, down regulation of PKD1 increases the proliferation and invasion of prostatic cells as well as induces epithelial to mesenchymal transition. PKD1 also influences AR transcriptional activity. METHODS In order to study the role of the PKD1-β-catenin-AR axis in progressive PCa, we transfected androgen sensitive LNCaP cells with one of three constructs: wild type β-catenin, T120 phosphorylated-β-catenin, or an empty vector. Chromatin Immunoprecipitation (CHIP) assay demonstrated a β-catenin and PKD1 transcription site association, which was subsequently abolished following mutation of T120-β-catenin to its unphosphorylated form. RESULTS Western blot experiments on all groups of transfected cells showed the nuclear translocation of T120 phosphorylated-β-catenin mutant transfected cells were higher compared to cells transfected with wild type-β-catenin or an empty vector, confirming increased levels of ABC in the nucleus. Interestingly, the expression of AR in cells transfected with T120 phosphorylated-β-catenin mutant was significantly lower compared to controls. Despite a decrease in AR activity, the expression of androgen response genes in the presence of androgen was significantly increased in the mutant transfected cells compared to controls, which suggests that ABC could activate androgen response genes independent from AR. CONCLUSIONS In conclusion, our study has identified several novel findings: 1) ABC is associated with the PKD1 transcription site suggesting a possible role for β-catenin in transcriptional regulation of PKD1, 2) the T120-β-catenin mutant down regulates AR expression, suggesting that phosphorylation of T120 by PKD1 is necessary for co-activation of AR expression by β-catenin and, 3) there exists a novel complex autoregulatory mechanism of PKD1, AR, and β-catenin expression, transport, and function. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e875 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Bita Nick Kholgh More articles by this author Michael B. Rothberg More articles by this author Sittadjody Sivanandane More articles by this author Xiaolan Fang More articles by this author K.C. Balaji More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...