Paradoxical roles of dual oxidases in cancer biology

Little, Andrew C.; Sulovari, Arvis; Danyal, Karamatullah; Heppner, David E.; Seward, David J.; Vliet, Albert van der

doi:10.1016/j.freeradbiomed.2017.05.024

Cited by 38 publications

(41 citation statements)

References 259 publications

(344 reference statements)

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“…NOX enzymes are often dysregulated in various cancers (Little et al ., ). Overexpression of DUOX2/DUOXA2 during ulcerative colitis is thought to be responsible for oxidative DNA damage as a predisposing factor for development of colon cancer (MacFie et al ., ).…”

Section: Duox In Disease Pathologymentioning

confidence: 97%

Dual oxidase: a novel therapeutic target in allergic disease

Vliet

Danyal

Heppner

2018

British J Pharmacology

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NADPH oxidases (NOXs) represent a family of enzymes that mediate regulated cellular production of reactive oxygen species (ROS) and play various functional roles in physiology. Among the NOX family, the dual oxidases DUOX1 and DUOX2 are prominently expressed in epithelial cell types at mucosal surfaces and have therefore been considered to have important roles in innate host defence pathways. Recent studies have revealed important insights into the host defence mechanisms of DUOX enzymes, which control innate immune response pathways in response to either microbial or allergic triggers. In this review, we discuss the current level of understanding with respect to the biological role(s) of DUOX enzymes and the unique role of DUOX1 in mediating innate immune responses to epithelial injury and allergens and in the development of allergic disease. These novel findings highlight DUOX1 as an attractive therapeutic target, and opportunities for the development of selective inhibitor strategies will be discussed. AbbreviationsCPZ, chlorpromazine; DPI, diphenylene iodonium; DUOX, dual oxidase; DUOXA, dual oxidase maturation factor; EGFR, EGF receptor; ER, endoplasmic reticulum; HDM, house dust mite; ILC2, type 2 innate lymphoid cell; LPO, lactoperoxidase; MPO, myeloperoxidase; NOX, NADPH oxidase; NOXA, NOX activator; PDB, protein database; PHD, peroxidase homology domain; ROS, reactive oxygen species; TK, tyrosine kinase; TLR, toll-like receptor; TPO, thyroperoxidase; TRX, thioredoxin IntroductionThe concept of oxidative stress has been widely embraced as a major factor in disease pathology and has fuelled a billion dollar industry based on antioxidant dietary supplements. However, clinical studies using antioxidant supplementation strategies have generally been unsuccessful in attenuating disease risk or progression, and antioxidant supplementation was in some cases found to even worsen pathological outcomes (Ghezzi et al., 2017). This lack of success likely relates to the flawed concept of oxidative stress as a pharmacological target. First, oxidative stress can be brought about by a range of ROS (the commonly used acronym to define this group of reactive metabolites), which can originate from external sources (e.g. environmental pollution and metabolism of xenobiotics) or be generated endogenously by various enzymatic systems, in some cases in a regulated and deliberate fashion to serve important biological functions [e.g. by activation of NADPH oxidases (NOXs)]. Therefore, generic non-selective approaches that indiscriminately suppress ROS may not have the desired outcome. A second flaw with such generic antioxidant approaches is the fact that ROS represent a diverse group of reactive metabolites that each have unique (bio)chemical properties, and it is often unclear to what extent antioxidant supplements counter the action of individual ROS species. To clarify this, it is helpful to distinguish primary from secondary ROS, with primary ROS representing the initial products of (enzymatic) O 2 reduction [i.e. superoxi...

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Section: Duox In Disease Pathologymentioning

confidence: 97%

Dual oxidase: a novel therapeutic target in allergic disease

Vliet

Danyal

Heppner

2018

British J Pharmacology

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“…In line with this, antioxidants (including NAC that abrogates RIR), which have been proposed to protect against carcinogenesis, in fact foster lung carcinomas and metastasis (Breau et al, 2019;Le Gal et al, 2015;Wiel et al, 2019). More generally, defect in each of the players of the "Low-stress" response described here (NF-κB, PARP1, FOXO1, DUOX1 and DUOX2) share common phenotypes, such as defects in cell homeostasis and metabolism, ageing and cancer predisposition (Ewald, 2018;Tia et al, 2018;Tilstra et al, 2011;Vida et al, 2016;Little et al, 2017;Park & Hong, 2016;Pires et al, 2018). `…”

Section: Discussionmentioning

confidence: 96%

“…In worms, NADPH oxidases trigger redox signaling that favors resistance to oxidative stress and promotes longevity (Ewald et al, 2017), supporting our interpretation. In humans, while various NADPH oxidases are often upregulated in cancers, only DUOX1 and DUOX2, which produce RIR in primary cells (see Figure 3A-C), are lost in different kinds of tumors (Little et al, 2017), highlighting the protective effects of the DUOX1-and DUOX2-controlled ROS. In line with this, antioxidants (including NAC that abrogates RIR), which have been proposed to protect against carcinogenesis, in fact foster lung carcinomas and metastasis (Breau et al, 2019;Le Gal et al, 2015;Wiel et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

An adaptive pre-DNA-damage-response protects genome integrity

Ragu

Matos-Rodrigues

Droin

et al. 2020

Preprint

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The DNA damage response (DDR) interrupts cell cycle progression to restore genome integrity. However, unchallenged proliferating cells are continually exposed to endogenous stress, raising the question of a stress-threshold for DDR activation. Here, we identified a stress threshold below which primary human fibroblasts, activate a cellautonomous response that not activates full DDR and not arrests cell cycle progression,.We characterized this "pre-DDR" response showing that it triggers the production of reactive oxygen species (ROS) by the NADPH oxidases DUOX1 and DUOX2, under the control of NF-κB and PARP1. Then, replication stress-induced ROS (RIR) activates the FOXO1 detoxifying pathway, preventing the nuclear accumulation of the pre-mutagenic 8-oxoGuanine lesion, upon endogenous as well as exogenous pro-oxidant stress.Increasing the replication stress severity above the threshold triggers the canonical DDR, leading to cell cycle progression arrest, but also to RIR suppression. These data reveal that cells adapt their response to stress severity, unveiling a tightly regulated "pre-DDR" adaptive response that protects genome integrity without arresting cell cycle progression.

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“…Redox biology is an area of great interest for cell biological responses in health and disease (Little et al 2017). Two major cellular organelles involved in reactive oxygen species (ROS) signaling are mitochondria and peroxisomes.…”

Section: Rotenone Effect On Peroxisomal Dynamics Mediated By Microtubmentioning

confidence: 99%

“…

thus offers a novel means to monitor and image fluorescently labeled neurons in deep regions of an awake and active rat.

Rotenone effect on peroxisomal dynamics mediated by microtubulesRedox biology is an area of great interest for cell biological responses in health and disease (Little et al 2017). Two major cellular organelles involved in reactive oxygen species (ROS) signaling are mitochondria and peroxisomes.

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mentioning

confidence: 99%

In focus in HCB

Taatjes

Roth

2017

Histochem Cell Biol

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thus offers a novel means to monitor and image fluorescently labeled neurons in deep regions of an awake and active rat. Rotenone effect on peroxisomal dynamics mediated by microtubulesRedox biology is an area of great interest for cell biological responses in health and disease (Little et al. 2017). Two major cellular organelles involved in reactive oxygen species (ROS) signaling are mitochondria and peroxisomes. Like many intracellular organelles, these organelles are also known to interact dynamically with one another in what is referred to as the "peroxisome-mitochondria connection" (Schrader et al. 2015). Although effects of the generation of oxidative stress in peroxisomes on mitochondrial function and morphology are well known, very little is known concerning potential effects of mitochondrial-derived oxidative stress on peroxisomal structure or function. To address this issue, Passmore et al. (2017) have performed experiments to examine effects of the complex I inhibitor rotenone on membrane dynamics occurring between mitochondria and peroxisomes. Using fluorescence microscopy, including quantitative assessment of ROS production with H 2 DCFDA, and immunoblotting they found that rotenone treatment had substantial effects on both peroxisomes and mitochondria in COS-7 cells. With respect to peroxisomes, rotenone affected both morphology and intracellular distribution through a mechanism independent of mitochondrial generated oxidative stress, but dependent upon microtubule destabilization. Interestingly, in contrast, the opposite situation occurred with the effect of rotenone on mitochondrial morphology: these effects were dependent upon the generation of ROS, but independent of microtubule stabilization. New system for monitoring brain neuronal activity in moving ratsOne of the great challenges in live animal imaging is the accurate recording of brain neuronal activity in a free-moving animal. Although multiphoton confocal microscopy has been used successfully to image more peripheral regions of the brain (Kerr et al. 2005), deeper regions remain inaccessible. Iijima et al. (2017) have now developed a system consisting of (1) a single optical fiber for recording neuronal activity via eGFP expression (linked to gonadotropin releasing hormone), and (2) a newly designed animal cage whereby the floor rotates in response to head movements, thus minimizing animal movement-derived stress on the optical fiber, for monitoring and imaging via fluorescence structures deep in the brain. This system allowed real-time fluorescence monitoring in awake and active animals over several days. By replacing the animal's water with a mild saline solution (to induce dehydration), they found an increase in eGFP fluorescence intensity in the paraventricular nucleus region. To refine their system to allow recording from individual neurons, the authors replaced the original optical fiber with a bundle containing approximately 3000 thin optical fibers and connected to an upright fluorescence microscope. Using this higher resolution ...

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Paradoxical roles of dual oxidases in cancer biology

Cited by 38 publications

References 259 publications

Dual oxidase: a novel therapeutic target in allergic disease

Dual oxidase: a novel therapeutic target in allergic disease

An adaptive pre-DNA-damage-response protects genome integrity

In focus in HCB

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