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      The role of dual oxidases in physiology and cancer

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          Abstract

          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 H2O2 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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          The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.

          Karen Bedard, Karl-Heinz Krause (2007)
          For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91(phox)), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX activity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.
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            Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement.

            Sebastian Altenhöfer, Kim A Radermacher, Pamela W. M. Kleikers … (2015)
            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.

              Bernard Lassègue, Kathy K. Griendling (2010)
              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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                Author and article information

                Journal
                Journal ID (publisher-id): gmb
                Title: Genetics and Molecular Biology
                Abbreviated Title: Genet. Mol. Biol.
                Publisher: Sociedade Brasileira de Genética (Ribeirão Preto, SP, Brazil )
                ISSN (Print): 1415-4757
                ISSN (Electronic): 1678-4685
                Publication date (Print and electronic): 2020
                Volume: 43
                Issue: 1 suppl 1
                Electronic Location Identifier: e20190096
                Affiliations
                [1] Rio de Janeiro Rio de Janeiro orgnameUniversidade Federal do Rio de Janeiro orgdiv1Instituto de Biofísica Carlos Chagas Filho Brazil
                Article
                Publisher ID: S1415-47572020000200313 Publisher ID: S1415-4757(20)04300100313
                DOI: 10.1590/1678-4685/gmb-2019-0096
                SO-VID: cc92e253-d632-41e4-8958-d7704cffd7e5
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                Date received : 20 March 2019
                Date accepted : 24 January 2020
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 90, Pages: 0
                Product

                SciELO Brazil


                Keywords: Dual oxidases,NADPH oxidases,reactive oxygen species,oxidative stress,cancer
                Data availability:
                Keywords: Dual oxidases, NADPH oxidases, reactive oxygen species, oxidative stress, cancer

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