TY - JOUR T1 - Modulation of PGE<sub>2</sub>-induced EP4 Expression on <em>Snail</em> Signaling and the Impact on Epithelial-Mesenchymal Transition: Significance of EP4 Antagonism JF - Anticancer Research JO - Anticancer Res SP - 4347 LP - 4357 VL - 31 IS - 12 AU - HYE NA KIM AU - NARAYANAN K. NARAYANAN AU - SALAMIA LASANO AU - BHAGAVATHI NARAYANAN Y1 - 2011/12/01 UR - http://ar.iiarjournals.org/content/31/12/4347.abstract N2 - Background: Although significant accumulation of prostaglandin E2 (PGE2) in the human prostate cancer tissues has been reported, there is lack of substantial evidence regarding the key role of PGE2-induced E-prostanoid-4 receptor (EP4) on Snail, a master regulator of epithelial mesenchymal transition (EMT). In this study, we investigated a novel connection between PGE2-induced EP4 and Snail (encodes DNA binding zinc finger protein that acts as transcriptional repressor) signaling in prostate cancer. Materials and Methods: To investigate the key role of serum PGE2, EP4, p-Akt and Snail in prostate cancer progression, we used prostate-specific phosphatase and tensin homolog (PTEN)-knockout (PTEN-KO) mice of different age groups from 4 to 28 weeks. To determine the EP4-specific interaction with Snail in prostate cancer, we used cell-based assays, including siRNA knockdown, and treatment with EP4 antagonist. Results: An interaction between EP4 with Snail was evident in prostate-specific PTEN-KO mice that showed an elevated level of PGE2 in the serum and of EP4, p-Akt and Snail in the tissues. Prostate cancer cells transfected with EP4-siRNA and treatments with EP4 antagonist suggest a link between EP4, and Snail activation, potentially via p-Akt. Cells treated with EP4 antagonist exhibited a significant decrease in Snail, mesenchymal markers and cell migration, and cell cycle arrest with a gain in E-cadherin levels. Conclusion: Our findings provide key evidence that support there being a role of PGE2/EP4/p-Akt in Snail signaling and conferring cell survival advantage. Cancer progression via EMT can be reversed by an EP4 antagonist in this model of prostate cancer. ER -