title: Up-regulation and sustained activation of Stat1 are essential for interferon-gamma (IFN-gamma)-induced dual oxidase 2 (Duox2) and dual oxidase A2 (DuoxA2) expression in human pancreatic cancer cell lines.
abstract: Dual oxidase 2 is a member of the NADPH oxidase (Nox) gene family that plays a critical role in the biosynthesis of thyroid hormone as well as in the inflammatory response of the upper airway mucosa and in wound healing, presumably through its ability to generate reactive oxygen species, including H2O2. The recently discovered overexpression of Duox2 in gastrointestinal malignancies, as well as our limited understanding of the regulation of Duox2 expression, led us to examine the effect of cytokines and growth factors on Duox2 in human tumor cells. We found that exposure of human pancreatic cancer cells to IFN-γ (but not other agents) produced a profound up-regulation of the expression of Duox2, and its cognate maturation factor DuoxA2, but not other members of the Nox family. Furthermore, increased Duox2/DuoxA2 expression was closely associated with a significant increase in the production of both intracellular reactive oxygen species and extracellular H2O2. Examination of IFN-γ-mediated signaling events demonstrated that in addition to the canonical Jak-Stat1 pathway, IFN-γ activated the p38-MAPK pathway in pancreatic cancer cells, and both played an important role in the induction of Duox2 by IFN-γ. Duox2 up-regulation following IFN-γ exposure is also directly associated with the binding of Stat1 to elements of the Duox2 promoter. Our findings suggest that the pro-inflammatory cytokine IFN-γ initiates a Duox2-mediated reactive oxygen cascade in human pancreatic cancer cells; reactive oxygen species production in this setting could contribute to the pathophysiologic characteristics of these tumors.
authors.affiliation: Laboratory of Molecular Pharmacology of the Center for Cancer Research, Division of Cancer Treatment and Diagnosis, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Smitha
authors.initials: S
authors.lastname: Antony
authors.forename: Agnes
authors.initials: A
authors.lastname: Juhasz
authors.forename: Jiamo
authors.initials: J
authors.lastname: Lu
authors.forename: Yun
authors.initials: Y
authors.lastname: Ge
authors.forename: Guojian
authors.initials: G
authors.lastname: Jiang
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Roy
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000074623:Dual Oxidases; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011485:Protein Binding / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C513411:DUOXA2 protein, human; D008565:Membrane Proteins; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C007517:diphenyleneiodonium; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human