Up-regulation and Sustained Activation of Stat1 Are Essential for Interferon-γ (IFN-γ)-induced Dual Oxidase 2 (Duox2) and Dual Oxidase A2 (DuoxA2) Expression in Human Pancreatic Cancer Cell Lines

Wu, Yongzhong; Antony, Smitha; Juhász, Ágnes; Lu, Jiamo; Ge, Yun; Jiang, Guojian; Roy, Krishnendu; Doroshow, James H.

doi:10.1074/jbc.m110.191031

Cited by 72 publications

(71 citation statements)

References 52 publications

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“…Similarly, cotreatment with IFNg, another stimulus for DUOX2 expression, did not further enhance promoter activity ( Figure E5). This may also reflect a promoter that is maximally stimulated, but more likely, the IFN-g regulatory region is outside this bidirectional promoter region (40). Consistent with that notion, we were unable to locate IFN-responsive sites contained within the promoter region that we isolated for these studies.…”

Section: Discussionsupporting

confidence: 62%

Dual Oxidase 2 Bidirectional Promoter Polymorphisms Confer Differential Immune Responses in Airway Epithelia

Linderholm

Grasberger

et al. 2012

Am J Respir Cell Mol Biol

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The dual oxidase enzymes, DUOX, localized to the respiratory tract epithelium, are important components of innate host defense against bacteria and virus. However, little is known regarding the regulation of DUOX transcription. To better understand DUOX2-mediated mechanisms of antiviral host defense in the airway epithelium, we designed a bidirectional promoter luciferase reporter system to identify important cis-regulatory regions in the human DUOX2/DUOXA2 promoter. In this report, we demonstrate that the genomic region between the translation start sites of DUOX2 and DUOXA2 functions as a bidirectional promoter in human airway tissue. We also identified key regulatory regions on the DUOX2/ DUOXA2 promoter that were necessary for both bidirectional and unidirectional transcriptional activity. Importantly, we discovered two functionally important single-nucleotide polymorphisms (SNPs) within the promoter that differentially regulated DUOX2/DUOXA2 transcription in response to exogenous double-stranded DNA. One of these SNPs, rs269855 (enriched in people of African descent), conferred the highest level of DUOX2 promoter activity. The clinical sequelae for individuals who carry this polymorphism remain to be determined.Keywords: airway; bidirectional promoter; dual oxidase; single-nucleotide polymorphism; virusThe respiratory tract epithelium is the central component of airway host defense. It is elegantly equipped to protect us from invading organisms through its mucus layer, tight epithelial barrier, air-surface liquid rich in antimicrobial peptides, and Toll-like or nucleotide oligomerization domain-like receptors that can induce inflammatory cytokines and recruit inflammatory cells (1, 2). Mounting evidence suggests that the hydrogen peroxide (H 2 O 2 ) specifically generated in airway epithelial cells by the nicotinamide adenine dinucleotide phosphate-reduced oxidase enzymes dual oxidase 1 or 2 (DUOX1 or DUOX2) is critical for many of these functions (3, 4).The initial and best characterized role of DUOX in host defense involves the production of H 2 O 2 , which serves as a substrate for lactoperoxidase (LPO) to oxidize thiocyanate (SCN 2 ) to hypothiocyanate (5, 6). When this oxidative antimicrobial model is tested in vitro, all three components (DUOX, LPO, and SCN 2 ) are essential for the effective killing of both grampositive and gram-negative bacteria (7-10). Moreover, the in vivo localization of these components is highly consistent with the proposed model (10). Recently, Fischer and colleagues demonstrated that this same oxidative system, by substituting I 2 for the pseudohalide SCN 2 , resulted in the production of virusinactivating hypoiodous acid (11), which suggests that DUOX is critical for the direct inactivation of bacteria and virus (12, 13). In addition to its immediate antimicrobial effects, DUOXgenerated H 2 O 2 is implicated in critical signaling roles for many other host defense functions of the respiratory tract epithelium. These include mucus generation through epidermal growth factor rec...

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Section: Discussionsupporting

confidence: 62%

Dual Oxidase 2 Bidirectional Promoter Polymorphisms Confer Differential Immune Responses in Airway Epithelia

Linderholm

Grasberger

et al. 2012

Am J Respir Cell Mol Biol

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“…To probe whether the iodonium analogs might affect the proliferation of HT-29 cells by inhibiting ROS production, HT-29 cells were treated with analog concentrations ranging from 10 to 1000 nM for 24 h. Whole cell intracellular ROS production was measured with the cell-permeant indicator 5- and 6-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate (CM-H 2 -DCF-DA) and quantified by analytical cytometry, as described previously [36]. Pre-treatment of HT-29 cells with 50 nM DPI, 104 , 392 , or 428 produced a left-shift (decrease) in DCF fluorescence compared to vehicle-treated control cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases

Risbood

Kane

et al. 2017

Biochemical Pharmacology

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The NADPH oxidases (NOXs) play a recognized role in the development and progression of inflammation-associated disorders, as well as cancer. To date, several NOX inhibitors have been developed, through either high throughput screening or targeted disruption of NOX interaction partners, although only a few have reached clinical trials. To improve the efficacy and bioavailability of the iodonium class NOX inhibitor diphenylene iodonium (DPI), we synthesized 36 analogs of DPI, focusing on improved solubility and functionalization. The inhibitory activity of the analogs was interrogated through cell viability and clonogenic studies with a colon cancer cell line (HT-29) that depends on NOX for its proliferative potential. Lack of altered cellular respiration at relevant iodonium analog concentrations was also demonstrated. Additionally, inhibition of ROS generation was evaluated with a luminescence assay for superoxide, or by Amplex Red® assay for H2O2 production, in cell models expressing specific NOX isoforms. DPI and four analogs (NSCs 740104, 751140, 734428, 737392) strongly inhibited HT-29 cell growth and ROS production with nanomolar potency in a concentration-dependent manner. NSC 737392 and 734428, which both feature nitro functional groups at the meta position, had >10-fold higher activity against ROS production by cells that overexpress dual oxidase 2 (DUOX2) than the other compounds examined (IC50 ≈ 200–400 nM). Based on these results, we synthesized and tested NSC 780521 with optimized potency against DUOX2. Iodonium analogs with anticancer activity, including the first generation of targeted agents with improved specificity against DUOX2, may provide a novel therapeutic approach to NOX-driven tumors.

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“…NOX-mediated reactive oxygen species (ROS) contribute to various liver diseases, including chronic hepatitis,6 alcohol-induced liver disease,7 cholestatic liver injury,8 hepatic fibrosis,9–11 and HCC 12. NOX-dependent ROS production differs with both tumor origin and NOX isoform 13. The NOX family promotes angiogenesis and is associated with the metastatic potential of many solid tumors 14.…”

Section: Introductionmentioning

confidence: 99%

NADPH Oxidase 1 and NADPH Oxidase 4 Have Opposite Prognostic Effects for Patients with Hepatocellular Carcinoma after Hepatectomy

Paik

Yang

et al. 2016

Gut and Liver

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Background/AimsNicotinamide adenine dinucleotide phosphate oxidase (NOX)-mediated reactive oxygen species contribute to various liver diseases, including hepatocellular carcinoma (HCC). Uncertainties remain regarding the prognostic relevance of NOX1 and NOX4 protein expression in HCC.MethodsNOX1 and NOX4 protein expression was examined by using immunohistochemistry in tumor tissue from 227 HCC patients who underwent hepatectomy.ResultsHigh immunoreactivity for NOX1 was observed in 197 (86.8%) of the 227 HCC cases and low immunoreactivity for NOX4 in 112 (49.3%). NOX1 and NOX4 proteins had opposite prognostic effects. High NOX1 expression was an independent predictor of both shorter recurrence-free survival (RFS) (p<0.01) and shorter overall survival (OS) (p=0.01). Low NOX4 expression was an independent predictor of both shorter RFS (p<0.01) and shorter OS (p=0.01). Subgroup analysis showed that, among patients with normal α-fetoprotein levels, patients with tumor size ≤5.0 cm and patients in Barcelona Clinic Liver Cancer stage A, high NOX1 expression had unfavorable effects on RFS, whereas low NOX4 expression had unfavorable effects on both RFS and OS.ConclusionsThese findings demonstrated that NOX1 and NOX4 protein expression had opposite prognostic effects for HCC patients. Moreover, both proteins had prognostic value in HCC patients with normal α-fetoprotein levels or with early-stage HCC.

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Up-regulation and Sustained Activation of Stat1 Are Essential for Interferon-γ (IFN-γ)-induced Dual Oxidase 2 (Duox2) and Dual Oxidase A2 (DuoxA2) Expression in Human Pancreatic Cancer Cell Lines

Cited by 72 publications

References 52 publications

Dual Oxidase 2 Bidirectional Promoter Polymorphisms Confer Differential Immune Responses in Airway Epithelia

Dual Oxidase 2 Bidirectional Promoter Polymorphisms Confer Differential Immune Responses in Airway Epithelia

Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases

NADPH Oxidase 1 and NADPH Oxidase 4 Have Opposite Prognostic Effects for Patients with Hepatocellular Carcinoma after Hepatectomy

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