475 RECIPROCAL REGULATION OF SLUG AND ANDROGEN RECEPTOR FACILITATES PROSTATE CANCER TO ACQUIRE CASTRATION RESISTANT AND STEM-LIKE PHENOTYPES (2012)

You have accessJournal of UrologyProstate Cancer: Basic Research III1 Apr 2012475 RECIPROCAL REGULATION OF SLUG AND ANDROGEN RECEPTOR FACILITATES PROSTATE CANCER TO ACQUIRE CASTRATION RESISTANT AND STEM-LIKE PHENOTYPES Kaijie Wu, Crystal Gore, Lin Yang, Gleave Martin, Rey-Chen Pong, Jer-Tsong Hsieh, and Dalin He Kaijie WuKaijie Wu Xi'an, China, People's Republic of More articles by this author , Crystal GoreCrystal Gore Dallas, TX More articles by this author , Lin YangLin Yang Xi'an, China, People's Republic of More articles by this author , Gleave MartinGleave Martin Vancouver, Canada More articles by this author , Rey-Chen PongRey-Chen Pong Dallas, TX More articles by this author , Jer-Tsong HsiehJer-Tsong Hsieh Dallas, TX More articles by this author , and Dalin HeDalin He Xi'an, China, People's Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.544AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Castration resistant prostate cancer (CRPC) is eventually incurable; however, its cell origin and characteristics are still poorly understood. Although the onset of CRPC is an inevitable outcome from hormonal therapy, androgen receptor (AR) hyperactivation is often associated with CRPC. There are several mechanisms such as gene amplification, mutation and splice variants. In this study, we report a new mechanism that the interaction between Slug and AR promote castration resistance of PCa cells with stem-like phenotypes. METHODS Slug gene regulation by AR was determined in three AR-positive PCa cells (LNCaP, C4-2 and CWR22RV1) with quantitative RT-PCR and western blot. A series of biochemical, molecular and cell biologic methods were employed to characterize the impacts of Slug on AR in PCa cells. Also, xenograft model and clinical specimens were used to validate in vitro results. RESULTS Slug appeared to be an androgen responsive gene in AR-positive PCa cells, and the presence of constitutively active AR splice variants often found in CRPC could also induce Slug expression. On the other hand, Slug formed a complex with either wild type AR or its splicing variants by stabilizing AR protein and enhancing AR transcriptional activities with or without androgen. The presence of this complex also increased in vitro growth of PCa in the absence of androgen, and provided the growth advantage of PCa cells to resist castration in xenograft animal model. We also noticed that Slug was able to increase stem cell phenotypes in PCa cells in which Slug-AR complex directly bound to the promoter region of two stem cell markers (i.e., CD117 and CD44) and increased their gene expression. Immunostaining of Slug and AR in three tissue microarrays unveiled a significant correlation of the expression of these two proteins during PCa progression. In addition, data from several cDNA microarrays indicated a positive correlation of mRNA expression between Slug and CD44 or CD117 in human clinical specimens. CONCLUSIONS A reciprocal regulation between Slug and AR plays a critical role in promoting the onset of CRPC in which both AR activation and stem-like phenotypes are highly elevated. Overall, this study unveils a new regulatory mechanism of AR with Slug as a novel co-activator, in which Slug appears to be a potent prognostic marker and therapeutic target for CRPC. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e194-e195 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.Metrics Author Information Kaijie Wu Xi'an, China, People's Republic of More articles by this author Crystal Gore Dallas, TX More articles by this author Lin Yang Xi'an, China, People's Republic of More articles by this author Gleave Martin Vancouver, Canada More articles by this author Rey-Chen Pong Dallas, TX More articles by this author Jer-Tsong Hsieh Dallas, TX More articles by this author Dalin He Xi'an, China, People's Republic of More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...