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      The role of dual oxidases in physiology and cancer

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          Abstract

          NOX/DUOX enzymes are transmembrane proteins that carry electrons through biological membranes generating reactive oxygen species. The NOX family is composed of seven members, which are NOX1 to NOX5 and DUOX1 and 2. DUOX enzymes were initially called thyroid oxidases, based on their high expression level in the thyroid tissue. However, DUOX expression has been documented in several extrathyroid tissues, mostly at the apical membrane of the salivary glands, the airways, and the intestinal tract, revealing additional cellular functions associated with DUOX-related H 2O 2 generation. In this review, we will briefly summarize the current knowledge regarding DUOX structure and physiological functions, as well as their possible role in cancer biology.

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          Most cited references 72

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          Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement.

          Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress. Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological role of specific NOX isoforms. Here, we discuss whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications. Modern NOX inhibitors have increased the evidence for pathophysiological roles of NADPH oxidases. However, in comparison to knockout mouse models, NOX inhibitors have limited isoform selectivity. Thus, their use does not enable clear statements on the involvement of individual NOX isoforms in a given disease. The development of isoform-selective NOX inhibitors and biologicals will enable reliable validation of specific NOX isoforms in disease models other than the mouse. Finally, GKT137831, the first NOX inhibitor in clinical development, is poised to provide proof of principle for the clinical potential of NOX inhibition.
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            NADPH oxidases: functions and pathologies in the vasculature.

            Reactive oxygen species are ubiquitous signaling molecules in biological systems. Four members of the NADPH oxidase (Nox) enzyme family are important sources of reactive oxygen species in the vasculature: Nox1, Nox2, Nox4, and Nox5. Signaling cascades triggered by stresses, hormones, vasoactive agents, and cytokines control the expression and activity of these enzymes and of their regulatory subunits, among which p22phox, p47phox, Noxa1, and p67phox are present in blood vessels. Vascular Nox enzymes are also regulated by Rac, ClC-3, Poldip2, and protein disulfide isomerase. Multiple Nox subtypes, simultaneously present in different subcellular compartments, produce specific amounts of superoxide, some of which is rapidly converted to hydrogen peroxide. The identity and location of these reactive oxygen species, and of the enzymes that degrade them, determine their downstream signaling pathways. Nox enzymes participate in a broad array of cellular functions, including differentiation, fibrosis, growth, proliferation, apoptosis, cytoskeletal regulation, migration, and contraction. They are involved in vascular pathologies such as hypertension, restenosis, inflammation, atherosclerosis, and diabetes. As our understanding of the regulation of these oxidases progresses, so will our ability to alter their functions and associated pathologies.
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              Regulation of ROS signal transduction by NADPH oxidase 4 localization

              Reactive oxygen species (ROS) function as intracellular signaling molecules in a diverse range of biological processes. However, it is unclear how freely diffusible ROS dictate specific cellular responses. In this study, we demonstrate that nicotinamide adenine dinucleotide phosphate reduced oxidase 4 (Nox4), a major Nox isoform expressed in nonphagocytic cells, including vascular endothelium, is localized to the endoplasmic reticulum (ER). ER localization of Nox4 is critical for the regulation of protein tyrosine phosphatase (PTP) 1B, also an ER resident, through redox-mediated signaling. Nox4-mediated oxidation and inactivation of PTP1B in the ER serves as a regulatory switch for epidermal growth factor (EGF) receptor trafficking and specifically acts to terminate EGF signaling. Consistent with this notion, PTP1B oxidation could also be modulated by ER targeting of antioxidant enzymes but not their untargeted counterparts. These data indicate that the specificity of intracellular ROS-mediated signal transduction may be modulated by the localization of Nox isoforms within specific subcellular compartments.
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                Author and article information

                Journal
                Genet Mol Biol
                Genet. Mol. Biol
                gmb
                Genetics and Molecular Biology
                Sociedade Brasileira de Genética
                1415-4757
                1678-4685
                20 May 2020
                2020
                : 43
                : 1 Suppl 1
                Affiliations
                [ 1 ]Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, RJ, Brazil.
                Author notes
                Send orrespondence to Rodrigo Soares Fortunato. Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho 373, CCS - Bloco G, Sala G0-031, Cidade Universitária - Ilha do Fundão, 21941-902 Rio de Janeiro, RJ, Brazil. E-mail: rodrigof@ 123456biof.ufrj.br .

                Author Contributions

                CCF and RSF contributed to all sections of the manuscript; RSF conceived the study. All authors read and approved the final version.

                The authors declare that they have no conflict of interest.

                Associate Editor: Nadja Souza Pinto

                Article
                00313
                10.1590/1678-4685/GMB-2019-0096
                7265977
                32453337

                License information: This is an open-access article distributed under the terms of the Creative Commons Attribution License (type CC-BY), which permits unrestricted use, distribution and reproduction in any medium, provided the original article is properly cited.

                Categories
                Review Article

                Molecular biology

                dual oxidases, cancer, oxidative stress, reactive oxygen species, nadph oxidases

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