title: NADPH oxidase NOX5-S and nuclear factor κB1 mediate acid-induced microsomal prostaglandin E synthase-1 expression in Barrett's esophageal adenocarcinoma cells.
abstract: 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.
authors: Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.
authors: Xiaoxu
authors: X
authors: Zhou
authors: Dan
authors: D
authors: Li
authors: Murray B
authors: MB
authors: Resnick
authors: Jack
authors: J
authors: Wands
authors: Weibiao
authors: W
authors: Cao
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001471:Barrett Esophagus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000071876:Prostaglandin-E Synthases; D015854:Up-Regulation
chemical_list: D008565:Membrane Proteins; D052002:NF-kappa B p50 Subunit; D000074664:NADPH Oxidase 5; D019255:NADPH Oxidases; C431571:NOX5 protein, human; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone