Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett's esophagus.
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.
Piazuelo
Elena
E
Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain. epiazor@unizar.es
Jiménez
Pilar
P
Strunk
Mark
M
Santander
Sonia
S
García
Asunción
A
Esteva
Francisco
F
Lanas
Angel
A
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
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