Authors: Song Xu Zhengyu Zhang Osamu Ogawa Takeshi Yoshikawa Hiromasa Sakamoto Noboru Shibasaki Takayuki Goto Liming Wang Naoki Terada
Publish Date: 2014/04/18
Volume: 70, Issue: 1, Pages: 521-527
Abstract
EP4 is one of the prostaglandin E2 receptors which is the most common prostanoid and is associated with inflammatory disease and cancer We previously reported that overexpression of EP4 was one of the mechanisms responsible for progression to castrationresistant prostate cancer and an EP4 antagonist ONOAE3208 in vivo suppressed the castrationresistant progression regulating the activation of androgen receptor The aim of this study was to analyze the association of EP4 with prostate cancer metastasis and the efficacy of ONOAE3208 for suppressing the metastasis The expression levels of EP4 mRNA were evaluated in prostate cancer cell lines LNCaP and PC3 EP4 overexpressing LNCaP was established and their cell invasiveness was compared with the control LNCaP LNCaP/mock The in vitro cell proliferation invasion and migration of these cells were examined under different concentrations of ONOAE3208 An in vivo bone metastatic mouse model was constructed by inoculating luciferase expressing PC3 cells into left ventricle of nude mice Their bone metastasis was observed by bioluminescent imaging with or without ONOAE3208 administration The EP4 mRNA expression levels were higher in PC3 than in LNCaP and EP4 overexpression of LNCaP cells enhanced their cell invasiveness The in vitro cell invasion and migration were suppressed by ONOAE3208 in a dosedependent manner without affecting cell proliferation The in vivo bone metastasis of PC3 was also suppressed by ONOAE3208 treatment EP4 expression levels were correlated with prostate cancer cell invasiveness and EP4 specific antagonist ONOAE3208 suppressed cell invasion migration and bone metastasis indicating that it is a potential novel therapeutic modality for the treatment of metastatic prostate cancer
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