Abstract
Mechanisms of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not known. Cycloxygenase-2 (COX2)-derived prostaglandin E2 (PGE2) has been shown to be important in esophageal tumorigenesis. We have shown that COX2 mediates acid-induced PGE2 production. The prostaglandin E synthase (PGES) responsible for acid-induced PGE2 production in BE, however, is not known. We found that microsomal PGES1 (mPGES1), mPGES2 and cytosolic PGES (cPGES) were present in FLO EA cells. Pulsed acid treatment significantly increased mPGES1 mRNA and protein levels, but had little or no effect on mPGES2 or cPGES mRNA, respectively. Knockdown of mPGES1 by mPGES1 siRNA blocked acid-induced increase in PGE2 production and thymidine incorporation. Knockdown of NOX5-S by NOX5 siRNA significantly inhibited acid-induced increase in mPGES1 expression, thymidine incorporation and PGE2 production. Overexpression of NOX5-S significantly increased the luciferase activity in FLO cells transfected with a NF-κB in vivo activation reporter plasmid pNF-κB-Luc. Knockdown of NF-κB1 p50 by p50 siRNA significantly decreased acid-induced increase in mPGES1 expression, thymidine incorporation and PGE2 production. Two novel NF-κB binding elements GGAGTCTCCC and CGGGACACCC were identified in the mPGES1 gene promoter. We conclude that mPGES1 mediates acid-induced increase in PGE2 production and cell proliferation. Acid-induced mPGES1 expression depends on activation of NOX5-S and NF-κB1 p50. Microsomal PGES1 may be a potential target to prevent or treat EA.
- Received October 26, 2012.
- Revision received February 25, 2013.
- Accepted February 25, 2013.
- The American Society for Pharmacology and Experimental Therapeutics