NADPH oxidase NOX5-S mediates acid-induced cyclooxygenase-2 expression via activation of NF-κB in Barrett's esophageal adenocarcinoma cells

Jin Si, Xiaoying Fu, Jose Behar, Jack Wands, David G. Beer, Rhonda F. Souza, Stuart J. Spechler, David Lambeth, Weibiao Cao

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

We have shown that the NADPH oxidase NOX5-S may play an important role in the progression from Barrett's esophagus to esophageal adenocarcinoma (EA) by increasing cell proliferation and decreasing apoptosis. However, the mechanism of the acid-induced NOX5-S-mediated increase in cell proliferation is not known. We found that, in SEG1 EA cells, the acid-induced increase in prostaglandin E2 (PGE2) production was mediated by activation of cyclooxygenase-2 (COX2) but not by COX1. Acid treatment increased intracellular Ca2+, and a blockade of intracellular Ca2+ increase inhibited the acid-induced increase in COX2 expression and PGE2 production. Knockdown of NOX5-S or NF-κB1 p50 by their small interfering RNA significantly inhibited acid-induced COX2 expression and PGE2 production in SEG1 cells. Acid treatment significantly decreased IκBα and increased luciferase activity when SEG1 cells were transfected with an NF-κB in vivo activation reporter plasmid, pNF-κB-Luc. In a novel Barrett's cell line overexpressing NOX5-S, IκBα was significantly reduced, and luciferase activity increased when these Barrett's cells were transfected with pNF-κB-Luc. Overexpression of NOX5-S in Barrett's cells significantly increased H 2O2 production, COX2 expression, PGE2 production, and thymidine incorporation. The increase in thymidine incorporation occurring in NOX5-S-overexpressing Barrett's cells or induced by acid treatment in SEG1 EA cells was significantly decreased by COX2 inhibitors or small interfering RNA. We conclude that acid-induced COX2 expression and PGE 2 production depend on an increase in cytosolic Ca2+ and sequential activation of NOX5-S and NF-κB in SEG1 cells. COX2-derived PGE2 production may contribute to NOX5-Smediated cell proliferation in SEG1 cells.

Original languageEnglish (US)
Pages (from-to)16244-16255
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number22
DOIs
StatePublished - Jun 1 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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