MP66-02 INHIBITION OF LIM-SH3 DOMAIN PROTEIN1 AUGMENTS THE ANTI-CANCER EFFECT OF ENZALUTAMIDE IN PROSTATE CANCER. (2015)

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2015MP66-02 INHIBITION OF LIM-SH3 DOMAIN PROTEIN1 AUGMENTS THE ANTI-CANCER EFFECT OF ENZALUTAMIDE IN PROSTATE CANCER. Takashi Dejima, Ario Takeuchi, Jeffrey Leong, Tabitha Tombe, Kevin Tam, Seiji Naito, Martin Gleave, and Christopher Ong Takashi DejimaTakashi Dejima More articles by this author , Ario TakeuchiArio Takeuchi More articles by this author , Jeffrey LeongJeffrey Leong More articles by this author , Tabitha TombeTabitha Tombe More articles by this author , Kevin TamKevin Tam More articles by this author , Seiji NaitoSeiji Naito More articles by this author , Martin GleaveMartin Gleave More articles by this author , and Christopher OngChristopher Ong More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2355AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES LIM-SH3 domain protein 1 (LASP1) has been shown to promote cancer progression and invasion in several malignancies. In prostate cancer, LASP1 is a strong predictor of early metastasis and correlates with invasion. However, the anti-tumor effects of LASP1 knockdown and the association between LASP1 and androgen receptor (AR) remain unclear. In this study, we investigated the anti-cancer activity of LASP1 knockdown in prostate cancer. METHODS The LASP1 expression in several prostate cancer cell lines was determined by Western blot analysis and quantitative reverse transcription-PCR. Silencing of LASP1 was achieved using siRNA. The tissue microarray (TMA) consisted of 164 patients' radical prostatectomies (Vancouver General Hospital). The effect of LASP1 knockdown in vivo was assessed by treating LASP1 antisense oligonucleotide (ASO) with mice in PC-3 xenograft model. RESULTS LASP1 is higher in PC-3 and DU145 cells than in LNCaP cells. Knockdown of LASP1 by siRNA reduced cell growth in PC-3 and DU145 cells. Flow cytometric analysis revealed that silencing of LASP1 induced G1 arrest, and was accompanied by an increase in p21 and a decrease in cyclinD1. Stable knockdown of LASP1 also reduced cell growth. Conversely, transient LASP1 overexpression in LNCaP promoted transition from G0/G1 to S phase and increased cyclinD1 and decreased p21. Additionally, stable overexpression of LASP1 in LNCaP, PC-3, and DU145 cells promoted cell growth and increased cyclinD1. In order to investigate the association between LASP1 and AR, we analyzed LASP1 expression in patients after radical prostatectomy. TMA data shows that LASP1 expression correlates with PSA recurrence after radical prostatectomy. Interestingly, LASP1 expression in TMA is increased after androgen-deprivation therapy (ADT). Consistent with TMA, LASP1 expression is higher in CRPC cancer cell lines (C4-2, VehA16 and VehD16) than in LNCaP cells. In addition, AR inhibition using Enzalutamide or siRNA induced LASP1 expression. Conversely, AR stimulation using R1881 suppressed LASP1 expression. LASP1 knockdown in combination with Enzalutamide showed synergistic effects in vitro. Systemic administration of LASP1 ASO in athymic mice injected with PC-3 cells significantly delays tumor progression. CONCLUSIONS These results suggest that inhibiting LASP1 through silencing technology holds promise as a novel therapeutic approach in the treatment of prostate cancer, and that this approach may have synergy with conventional anti-androgens. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e816 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takashi Dejima More articles by this author Ario Takeuchi More articles by this author Jeffrey Leong More articles by this author Tabitha Tombe More articles by this author Kevin Tam More articles by this author Seiji Naito More articles by this author Martin Gleave More articles by this author Christopher Ong More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...