PT  - JOURNAL ARTICLE
AU  - HYE NA KIM
AU  - NARAYANAN K. NARAYANAN
AU  - SALAMIA LASANO
AU  - BHAGAVATHI NARAYANAN
TI  - 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
DP  - 2011 Dec 01
TA  - Anticancer Research
PG  - 4347--4357
VI  - 31
IP  - 12
4099  - http://ar.iiarjournals.org/content/31/12/4347.short
4100  - http://ar.iiarjournals.org/content/31/12/4347.full
SO  - Anticancer Res2011 Dec 01; 31
AB  - 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.