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HORMONES AND SIGNALING

STAT5 mediates PAF-induced NADPH oxidase NOX5-S expression in Barrett's esophageal adenocarcinoma cells

Departments of ¹Medicine and ²Surgery, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island; ³Department of Surgery, Section of General Thoracic Surgery, University of Michigan Medical School, Ann Arbor, Michigan; and ⁴Department of Pathology, Emory University School of Medicine, Atlanta, Georgia

Submitted 26 June 2007 ; accepted in final form 12 October 2007

We have shown that NADPH oxidase NOX5-S is overexpressed in Barrett's esophageal adenocarcinoma (EA) cells and may contribute to the progression from Barrett's esophagus (BE) to EA presumably by increasing cell proliferation and decreasing apoptosis (Fu X, Beer DG, Behar J, Wands J, Lambeth D, Cao W. J Biol Chem 281: 20368–20382, 2006). The mechanism(s) of NOX5-S overexpression in EA, however, is not fully understood. In SEG1 EA cells we found that acid treatment significantly increased platelet-activating factor (PAF) production, which in turn markedly increased NOX5-S expression and hydrogen peroxide (H₂O₂) production. Knockdown of NOX5-S by NOX5-S small interfering RNA (siRNA) blocked PAF-dependent H₂O₂ production. PAF-dependent induction of NOX5-S expression and H₂O₂ production were significantly decreased by the MAPK kinase 1 inhibitor PD-98059, by the cytosolic phospholipase A₂ (cPLA₂) inhibitor AACOCF3, and by STAT5 downregulation with STAT5 siRNA. PAF significantly increased the phosphorylation of ERK1/2 MAPK, cPLA₂, and STAT5. Using inhibitors, we demonstrated that PAF-induced STAT5 phosphorylation depends on activation of ERK1/2 MAPK and cPLA₂, whereas PAF-induced cPLA₂ phosphorylation was associated with activation of ERK1/2 MAPK. Given that STAT5 bound to the c-sis-inducible element (TTCTGGTAA) of the NOX5-S promoter, overexpression of STAT5 significantly increased NOX5-S promoter activity. We conclude that acid-induced NOX5-S expression and H₂O₂ production is mediated in part by production of PAF in SEG1 EA cells, and that PAF-induced increase in NOX5-S expression depends on sequential activation of ERK MAP kinases, cPLA₂, and STAT5 in these cells.

platelet-activating factor; signaling; MAPK; cPLA₂; reactive oxygen species