title: Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett's esophagus.
abstract: Accumulating evidence suggests that COX-2-derived prostaglandin E(2) (PGE(2)) plays an important role in esophageal adenocarcinogenesis. Recently, PGE(2) receptors (EP) have been shown to be involved in colon cancer development. Since it is not known which receptors regulate PGE(2) signals in esophageal adenocarcinoma, we investigated the role of EP receptors using a human Barrett's-derived esophageal adenocarcinoma cell line (OE33). OE33 cells expressed COX-1, COX-2, EP(1), EP(2) and EP(4) but not EP(3) receptors as determined by real time RT-PCR and Western-blot. Treatment with 5-aza-dC restored expression, suggesting that hypermethylation is involved in EP(3) downregulation. Endogenous PGE(2) production was mainly due to COX-2, since this was significantly suppressed with COX-2 inhibitors (NS-398 and SC-58125), but not COX-1 inhibitors (SC-560). Cell proliferation ((3)H-thymidine uptake) was significantly inhibited by NS-398 and SC-58125, the EP(1) antagonist SC-51322, AH6809 (EP(1)/EP(2) antagonist), and the EP(4) antagonist AH23848B, but was not affected by exogenous PGE(2). However, treatment with the selective EP(2) agonist Butaprost or 16,16-dimethylPGE(2) significantly inhibited butyrate-induced apoptosis and stimulated OE33 cell migration. The effect of exogenous PGE(2) on migration was attenuated when cells were first treated with EP(1) and EP(4) antagonists. These findings suggest a potential role for EP selective antagonists in the treatment of esophageal adenocarcinoma.
authors.affiliation: Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain. epiazor@unizar.es
authors.forename: Elena
authors.initials: E
authors.lastname: Piazuelo
authors.forename: Pilar
authors.initials: P
authors.lastname: Jiménez
authors.forename: Mark
authors.initials: M
authors.lastname: Strunk
authors.forename: Sonia
authors.initials: S
authors.lastname: Santander
authors.forename: Asunción
authors.initials: A
authors.lastname: García
authors.forename: Francisco
authors.initials: F
authors.lastname: Esteva
authors.forename: Angel
authors.initials: A
authors.lastname: Lanas
mesh_terms: D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D001471:Barrett Esophagus / Q000473:pathology*; D015153:Blotting, Western; D002087:Butyrates; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000473:pathology*; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000378:metabolism
chemical_list: D002087:Butyrates; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; C115461:SC 560; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015064:16,16-Dimethylprostaglandin E2; D013936:Thymidine