NADPH Oxidase NOX5-S and Nuclear Factor κB1 Mediate Acid-Induced Microsomal Prostaglandin E Synthase-1 Expression in Barrett's Esophageal Adenocarcinoma Cells.
The mechanisms of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not known. Cycloxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) has been shown to be important in esophageal tumorigenesis. We have shown that COX-2 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. Knockdown of mPGES1 by mPGES1 small interfering RNA (siRNA) blocked acid-induced increase in PGE2 production and thymidine incorporation. Knockdown of NADPH oxidase, NOX5-S, a variant lacking calcium-binding domains, 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 nuclear factor κB (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.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y
thymidine PGE2 prostaglandin E2 PGE2 PGE2 PGE2 prostaglandin E PGE2 PGE2 thymidine NADPH calcium thymidine PGE2 NADPH Prostaglandin E nuclear factor κB Cycloxygenase-2 NF-κB NF-κB NF-κB1 p50 p50 mPGES1 COX-2 NF-κB binding elements GGAGTCTCCC CGGGACACCC mPGES1 gene promoter mPGES1 mPGES1 NOX5-S NF-κB1 p50 Microsomal PGES1 COX-2 prostaglandin E synthase PGES microsomal PGES1 mPGES1 mPGES2 cytosolic PGES cPGES mPGES1 mPGES2 cPGES mPGES1 mPGES1 NADPH oxidase NOX5-S calcium-binding domains NOX5 mPGES1 NOX5-S NADPH Oxidase NOX5-S Nuclear Factor κB1 Microsomal Prostaglandin E Synthase-1