MP49-08 WNT/β-CATENIN SIGNALLING IS A POTENTIAL THERAPEUTIC TARGET FOR CASTRATE-RESISTANT PROSTATE CANCER.

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2014MP49-08 WNT/β-CATENIN SIGNALLING IS A POTENTIAL THERAPEUTIC TARGET FOR CASTRATE-RESISTANT PROSTATE CANCER. Yoshiaki Kawano, Yoshihiro Maeda, Takanobu Motoshima, Takahisa Imamura, Wataru Takahashi, Yoshihiro Wada, Robert Kypta, and Masatoshi Eto Yoshiaki KawanoYoshiaki Kawano More articles by this author , Yoshihiro MaedaYoshihiro Maeda More articles by this author , Takanobu MotoshimaTakanobu Motoshima More articles by this author , Takahisa ImamuraTakahisa Imamura More articles by this author , Wataru TakahashiWataru Takahashi More articles by this author , Yoshihiro WadaYoshihiro Wada More articles by this author , Robert KyptaRobert Kypta More articles by this author , and Masatoshi EtoMasatoshi Eto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1109AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Wnt/β-catenin pathway is aberrantly activated in substantial fraction of castration-resistant prostate cancer (CRPC), therefore targeting this pathway may be effective therapeutic option for substantial fraction of CRPC patients. Objectives: We aimed to elucidate the effect of inhibiting Wnt/β-catenin pathway on prostate cancer cell growth and sensitising docetaxel-induced cytotoxicity in CRPC cells. Methods LNCaP cells stably expressing β-catenin shRNA in a doxycycline-inducible manner (LNCaP/TR-βi) were established by sequential stable transfection with the tetracycline repressor gene (tetR) and β-catenin shRNA under the control of the tetracycline operator sequence directly upstream of the H1 promotor. For animal study, male BALB/c strain nude mice were injected subcutaneously with LNCaP/TR-βi cells, followed by doxycycline (dox) administration in drinking water for β-catenin shRNA induction. IWR-1 endo and CCT036477 were used to analyse the effect of chemical inhibition of Wnt/β-catenin signaling. Results β-catenin shRNA induction by dox treatment markedly reduced LNCaP/TR-βi cell growth in vitro. LNCaP/TR-βi cells exhibited unexpected castration-resistant growth after transplantation into nude mice. However, β-catenin knockdown by dox administration significantly suppressed such in vivo growth as well. Such inhibitory effect of β-catenin knockdown against cellular proliferation was also observed in CRPC cell lines, such as DU145 and PC-3 cells, by siRNA transfection. These results suggest that Wnt/β-catenin plays a crucial role in proliferation of prostate cancer cells regardless of their androgen-dependence. Wnt/β-catenin inhibitors, IWR-1 endo and CCT036477, effectively phenocopied the depletion of β-catenin in prostate cancer cell, and augmented the cytotoxic effect of low-dose docetaxel in CRPC cells. Intriguingly, cell cycle analysis revealed that IWR-1 endo alone enriched G1 population but rather triggered mitotic catastrophe effectively in combination with low-dose docetaxel. Conclusions This study provides proof of concept that a) inhibiting β-catenin, by either knockdown or chemical inhibitors, suppresses prostate cancer cell growth, and b) targeting Wnt/β-catenin signaling pathway is a valid therapeutic strategy for CRPC. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e504-e505 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Yoshiaki Kawano More articles by this author Yoshihiro Maeda More articles by this author Takanobu Motoshima More articles by this author Takahisa Imamura More articles by this author Wataru Takahashi More articles by this author Yoshihiro Wada More articles by this author Robert Kypta More articles by this author Masatoshi Eto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...