MP70-11 REVERSE OF DOCETAXEL RESISTANCE IN PROSTATE CANCER VIA NOTCH SIGNALING INHIBITION

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2018MP70-11 REVERSE OF DOCETAXEL RESISTANCE IN PROSTATE CANCER VIA NOTCH SIGNALING INHIBITION Qiu Shi, Xiang Tu, Qiang Wei, and Lu Yang Qiu ShiQiu Shi More articles by this author , Xiang TuXiang Tu More articles by this author , Qiang WeiQiang Wei More articles by this author , and Lu YangLu Yang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2255AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Chemotherapeutic Docetaxel (Doc) is the standard of care for the hormone resistant prostate cancer (HRPC). However, many HRPC patients do not respond to Doc chemotherapy in a long-term treatment because the cancerous tissue acquires resistance to Doc treatment. The molecular mechanism underlying the development of Doc resistance in HRPC remains unclear. METHODS Human prostate cancer cell line DU145 were purchased and Doc resistant human prostate cancer cell line DU145/adr were generated by culturing cells with Docetaxel in a dose-escalation manner. Cell viability was determined by MTT assay kit. After enumeration of tumor stem-like cells in 3D fibrin gels, CD133 positive cells were selected by fluorescence-activated cell sorting. A Notch signaling pathway inhibitor was applied to combine with Doc to overcome the Doc resistance in HRPC. The ability to release doxorubicin from DU145 and DU145/adr cells was detected by HPLC. Quantitative real-time PCR and western blotting were performed for the detection of the target genes and proteins. RESULTS A subpopulation of prostate cancer cells, owing enhanced stem-like properties, was found in both prostate cancer cell line and HRPC patient tumor tissues, showed high resistance to Doc. The subpopulation of Doc resistance cells has up-regulation of Notch2 and activation of Notch signaling pathway, leading to the high tumor initiating ability and colony formation capability. Most importantly, the Notch signaling pathway up-regulates the expression of drug resistant associated gene ABCB1, which encodes P-GP, resulting in the Doc resistance. CONCLUSIONS Our results illustrated the role of a stem cell-like subpopulation of prostate cancer cells in Doc-resistance that is dependent on Notch signaling pathway activation. Importantly, regulation of Notch signaling was evident in samples derived from the tumors of HRPC patients indicating the clinical relevance of Notch as a potential Doc resistance biomarker. Furthermore, inhibition of Notch signaling pathway in Doc treatment regimens can re-sensitize cancer cells, revealing a potential therapeutic strategy in cases of HRPC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e938 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Qiu Shi More articles by this author Xiang Tu More articles by this author Qiang Wei More articles by this author Lu Yang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...