title: Modulation of PGE2-induced EP4 expression on snail signaling and the impact on epithelial-mesenchymal transition: significance of EP4 antagonism.
abstract: BACKGROUND
  Although significant accumulation of prostaglandin E(2) (PGE(2)) in the human prostate cancer tissues has been reported, there is lack of substantial evidence regarding the key role of PGE(2)-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 PGE(2)-induced EP4 and Snail (encodes DNA binding zinc finger protein that acts as transcriptional repressor) signaling in prostate cancer.
  
  
  METHODS
  To investigate the key role of serum PGE(2), 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 PGE(2) 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.
  
  
  CONCLUSIONS
  Our findings provide key evidence that support there being a role of PGE(2)/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.
authors.affiliation: New York University School of Medicine, Department of Environmental Medicine, Tuxedo, NY, USA.
authors.forename: Hye Na
authors.initials: HN
authors.lastname: Kim
authors.forename: Narayanan K
authors.initials: NK
authors.lastname: Narayanan
authors.forename: Salamia
authors.initials: S
authors.lastname: Lasano
authors.forename: Bhagavathi
authors.initials: B
authors.lastname: Narayanan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015232:Dinoprostone / Q000378:metabolism*; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007124:Immunoenzyme Techniques / Q000379:methods; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence / Q000379:methods; D011471:Prostatic Neoplasms / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D015232:Dinoprostone