677 IDENTIFICATION OF EP4 AS A POTENTIAL TARGET FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER USING A NOVEL XENOGRAFT MODEL

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2010677 IDENTIFICATION OF EP4 AS A POTENTIAL TARGET FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER USING A NOVEL XENOGRAFT MODEL Naoki Terada, Yosuke Shimizu, Tomomi Kamba, Takahiro Inoue, Atsushi Maeno, Takashi Kobayashi, Eijiro Nakamura, Toshiyuki Kamoto, Toshiya Kanaji, Takayuki Maruyama, Yoshiki Mikami, Yoshinobu Toda, Toshiyuki Matsuoka, Yasushi Okuno, Gozoh Tsujimoto, Shuh Narumiya, and Osamu Ogawa Naoki TeradaNaoki Terada Kyoto, Japan More articles by this author , Yosuke ShimizuYosuke Shimizu Kyoto, Japan More articles by this author , Tomomi KambaTomomi Kamba Kyoto, Japan More articles by this author , Takahiro InoueTakahiro Inoue Kyoto, Japan More articles by this author , Atsushi MaenoAtsushi Maeno Kyoto, Japan More articles by this author , Takashi KobayashiTakashi Kobayashi Kyoto, Japan More articles by this author , Eijiro NakamuraEijiro Nakamura Boston, MA More articles by this author , Toshiyuki KamotoToshiyuki Kamoto Miyazaki, Japan More articles by this author , Toshiya KanajiToshiya Kanaji Osaka, Japan More articles by this author , Takayuki MaruyamaTakayuki Maruyama Osaka, Japan More articles by this author , Yoshiki MikamiYoshiki Mikami Kyoto, Japan More articles by this author , Yoshinobu TodaYoshinobu Toda Kyoto, Japan More articles by this author , Toshiyuki MatsuokaToshiyuki Matsuoka Kyoto, Japan More articles by this author , Yasushi OkunoYasushi Okuno Kyoto, Japan More articles by this author , Gozoh TsujimotoGozoh Tsujimoto Kyoto, Japan More articles by this author , Shuh NarumiyaShuh Narumiya Kyoto, Japan More articles by this author , and Osamu OgawaOsamu Ogawa Kyoto, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1076AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are extremely limited and it is highly desirable to explore new therapeutic strategies based on a detailed understanding of molecular mechanisms for the progression to castration resistance. We have established a novel prostate cancer (PC) xenograft model, KUCaP-2, expressing wild-type androgen receptor (AR) and producing PSA. The xenograft tumors regress soon after castration and reproducibly regrow after 1-2 months without AR mutation, mimicking the clinical behavior of PC. The aim of the present study is to identify a novel therapeutic target against CRPC using this model. METHODS KUCaP-2 was established by the subcutaneous transplantation of local recurrent PC tumors into male nude mice. Xenograft tissues were collected during androgen-dependent growth (AD), castration-induced regression nadir (ND), and castration-resistant regrowth (CR) stages (n=4, each). Changes in gene expression profiles were examined using DNA microarray analysis. The expression levels of a candidate gene in 31 CRPC and 27 hormone-naïve PC (HNPC) clinical samples were examined by the immunohistochemistry and graded as none, weak, moderate and strong. Functional analyses of the candidate gene were performed using LNCaP cells. Effectiveness of the gene targeting therapy was investigated by the treatment against KUCaP-2. RESULTS The expression of prostaglandin E receptor EP4 subtype (EP4) was significantly up-regulated during the progression of castration resistance in KUCaP-2 tumors (ND/AD ratio=1.0; p=0.496, CR/ND ratio=15.7; p=0.029). In clinical samples EP4 expression grade of none/weak/moderate/strong were 10 (37%) / 17 (63%) / 0 (0%) / 0 (0%) in HNPC and 5 (16%) / 9 (29%) / 10 (32%) / 7 (22%) in CRPC patients (p=0.0001). EP4 over-expressing LNCaP (LNCaP-EP4) cells proliferated and produced PSA without androgen in vitro and in vivo. The androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated using RNA interference. A specific EP4 antagonist, ONO-AE3-208, significantly decreased intracellular cAMP levels and suppressed PSA production of LNCaP-EP4 cells in vitro (100nmol/l) and decelerated castration-resistant growth of LNCaP-EP4 and KUCaP-2 tumors in vivo (10mg/kg/day/IP). CONCLUSIONS EP4 over-expression, via AR activation, is one of the mechanisms for the castration-resistant progression of PC and the EP4 antagonist is a novel therapeutic modality for the treatment of CRPC. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e264-e265 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Naoki Terada Kyoto, Japan More articles by this author Yosuke Shimizu Kyoto, Japan More articles by this author Tomomi Kamba Kyoto, Japan More articles by this author Takahiro Inoue Kyoto, Japan More articles by this author Atsushi Maeno Kyoto, Japan More articles by this author Takashi Kobayashi Kyoto, Japan More articles by this author Eijiro Nakamura Boston, MA More articles by this author Toshiyuki Kamoto Miyazaki, Japan More articles by this author Toshiya Kanaji Osaka, Japan More articles by this author Takayuki Maruyama Osaka, Japan More articles by this author Yoshiki Mikami Kyoto, Japan More articles by this author Yoshinobu Toda Kyoto, Japan More articles by this author Toshiyuki Matsuoka Kyoto, Japan More articles by this author Yasushi Okuno Kyoto, Japan More articles by this author Gozoh Tsujimoto Kyoto, Japan More articles by this author Shuh Narumiya Kyoto, Japan More articles by this author Osamu Ogawa Kyoto, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Topic: Prostate Cancer Treatment and Research
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences