TY - JOUR
T1 - Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett's esophagus
AU - Piazuelo, Elena
AU - Jiménez, Pilar
AU - Strunk, Mark
AU - Santander, Sonia
AU - García, Asunción
AU - Esteva, Francisco
AU - Lanas, Angel
N1 - Funding Information:
This study was supported with grants FIS (02/3037), FIS (020638), CICYT (SAF 2003-08861) and Instituto de Salud Carlos III (C03/02).
PY - 2006/12
Y1 - 2006/12
N2 - Accumulating evidence suggests that COX-2-derived prostaglandin E2 (PGE2) plays an important role in esophageal adenocarcinogenesis. Recently, PGE2 receptors (EP) have been shown to be involved in colon cancer development. Since it is not known which receptors regulate PGE2 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, EP1, EP2 and EP4 but not EP3 receptors as determined by real time RT-PCR and Western-blot. Treatment with 5-aza-dC restored expression, suggesting that hypermethylation is involved in EP3 downregulation. Endogenous PGE2 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 (3H-thymidine uptake) was significantly inhibited by NS-398 and SC-58125, the EP1 antagonist SC-51322, AH6809 (EP1/EP2 antagonist), and the EP4 antagonist AH23848B, but was not affected by exogenous PGE2. However, treatment with the selective EP2 agonist Butaprost or 16,16-dimethylPGE2 significantly inhibited butyrate-induced apoptosis and stimulated OE33 cell migration. The effect of exogenous PGE2 on migration was attenuated when cells were first treated with EP1 and EP4 antagonists. These findings suggest a potential role for EP selective antagonists in the treatment of esophageal adenocarcinoma.
AB - Accumulating evidence suggests that COX-2-derived prostaglandin E2 (PGE2) plays an important role in esophageal adenocarcinogenesis. Recently, PGE2 receptors (EP) have been shown to be involved in colon cancer development. Since it is not known which receptors regulate PGE2 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, EP1, EP2 and EP4 but not EP3 receptors as determined by real time RT-PCR and Western-blot. Treatment with 5-aza-dC restored expression, suggesting that hypermethylation is involved in EP3 downregulation. Endogenous PGE2 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 (3H-thymidine uptake) was significantly inhibited by NS-398 and SC-58125, the EP1 antagonist SC-51322, AH6809 (EP1/EP2 antagonist), and the EP4 antagonist AH23848B, but was not affected by exogenous PGE2. However, treatment with the selective EP2 agonist Butaprost or 16,16-dimethylPGE2 significantly inhibited butyrate-induced apoptosis and stimulated OE33 cell migration. The effect of exogenous PGE2 on migration was attenuated when cells were first treated with EP1 and EP4 antagonists. These findings suggest a potential role for EP selective antagonists in the treatment of esophageal adenocarcinoma.
KW - Adenocarcinoma
KW - Barrett's esophagus
KW - COX-2
KW - EP receptors
KW - Prostaglandin E
UR - http://www.scopus.com/inward/record.url?scp=33750531865&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33750531865&partnerID=8YFLogxK
U2 - 10.1016/j.prostaglandins.2006.09.002
DO - 10.1016/j.prostaglandins.2006.09.002
M3 - Article
C2 - 17085323
AN - SCOPUS:33750531865
SN - 1098-8823
VL - 81
SP - 150
EP - 161
JO - Prostaglandins and Other Lipid Mediators
JF - Prostaglandins and Other Lipid Mediators
IS - 3-4
ER -