MP83-13 ZOLEDRONIC ACID SENSITIZES CASTRATION-RESISTANT PROSTATE CANCER CELLS TO RADIOTHERAPY AND CHEMOTHERAPY BY DOWNREGULATING STAT1

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II1 Apr 2017MP83-13 ZOLEDRONIC ACID SENSITIZES CASTRATION-RESISTANT PROSTATE CANCER CELLS TO RADIOTHERAPY AND CHEMOTHERAPY BY DOWNREGULATING STAT1 Takayuki Nakayama, Toshiki Kijima, Soichiro Yoshida, Fumitaka Koga, Kazunori Kihara, and Yasuhisa Fujii Takayuki NakayamaTakayuki Nakayama More articles by this author , Toshiki KijimaToshiki Kijima More articles by this author , Soichiro YoshidaSoichiro Yoshida More articles by this author , Fumitaka KogaFumitaka Koga More articles by this author , Kazunori KiharaKazunori Kihara More articles by this author , and Yasuhisa FujiiYasuhisa Fujii More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2581AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Management of castration-resistant prostate cancer (CPRC) remains challenging due to the inevitable emergence of resistance to treatments including radiotherapy (RT) and chemotherapy (CT). We previously reported that zoledronic acid (ZOL) clinically potentiates the antitumor effects of RT in patients with renal cell carcinoma (Kijima et al, BJU Int 2009) and that this radiosensitization could occur through the osteoclast-independent inhibition of signal transducer and activator of transcription 1 (STAT1) (Kijima et al, PLoS One 2013). As the association between STAT1 overexpression and treatment resistance has been reported in several cancers, we investigated whether STAT1 is associated with resistance to RT and CT in CRPC cells and whether ZOL could overcome this resistance by downregulating STAT1. METHODS Baseline expression of STAT1 was compared between androgen-dependent LNCaP cells and androgen-independent LNCaP (LNCaP-CR), PC3, and DU145 cells. The effect of ZOL on STAT1 expression was evaluated by Western blot and real-time PCR. The sensitizing effects of ZOL on RT and CT (docetaxel) were examined by clonogenic assay and MTS assay with combination index analysis. To confirm the importance of STAT1 on radio- and chemo-sensitization by ZOL, both siRNA knockdown and forced expression by cDNA transfection were performed. RESULTS STAT1 levels were higher in androgen-independent cell lines (PC3, DU145) than in LNCaP cells (Figure A). STAT1 was gradually upregulated in LNCaP as these cells acquired androgen independency through continuous androgen ablation (Figure B). ZOL decreased STAT1 at the protein level (Figure C) through proteasome-mediated degradation and sensitized PC3 and DU145 to both RT and CT. Functional siRNA knockdown of STAT1 resulted in the sensitization of DU145 to RT and CT. Forced expression of STAT1 in LNCaP cells rendered them resistant to those therapies. CONCLUSIONS ZOL sensitizes CRPC cells to RT and CT by downregulating STAT1. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1111 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Takayuki Nakayama More articles by this author Toshiki Kijima More articles by this author Soichiro Yoshida More articles by this author Fumitaka Koga More articles by this author Kazunori Kihara More articles by this author Yasuhisa Fujii More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...