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 over-expression of EP4 was one of the mechanisms responsible for progression to
castration-resistant
prostate cancer, and an EP4 antagonist
ONO-AE3-208 in vivo suppressed the
castration-resistant 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
ONO-AE3-208 for suppressing the
metastasis. The expression levels of EP4
mRNA were evaluated in
prostate cancer cell lines, LNCaP, and PC3. EP4 over-expressing 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
ONO-AE3-208. 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
ONO-AE3-208 administration. The EP4
mRNA expression levels were higher in PC3 than in LNCaP, and EP4 over-expression of LNCaP cells enhanced their cell invasiveness. The in vitro cell invasion and migration were suppressed by
ONO-AE3-208 in a dose-dependent manner without affecting cell proliferation. The in vivo bone
metastasis of PC3 was also suppressed by
ONO-AE3-208 treatment. EP4 expression levels were correlated with
prostate cancer cell invasiveness and EP4 specific antagonist
ONO-AE3-208 suppressed cell invasion, migration, and bone
metastasis, indicating that it is a potential novel therapeutic modality for the treatment of metastatic
prostate cancer.