bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2020‒02‒09
ten papers selected by
Laia Caja Puigsubira
Uppsala University


  1. Antioxid Redox Signal. 2020 Feb 01.
    Konaté MM, Antony S, Doroshow JH.
      SIGNIFICANCE: The primary function of NADPH oxidases (NOX1-5 and dual oxidases DUOX1/2) is to produce reactive oxygen species (ROS). If inadequately regulated, NOX-associated ROS can promote oxidative stress, aberrant signaling, and genomic instability. Correspondingly, NOX isoforms are known to be overexpressed in multiple malignancies, thus constituting potential therapeutic targets in cancer. Recent Advances: Multiple genetic studies aimed at suppressing the expression of NOX proteins in cellular and animal models of cancer have provided support for the notion that NOXs play a pro-tumorigenic role. Furthermore, large drug screens and rational design efforts have yielded inhibitor compounds, such as the diphenylene iodonium (DPI) analog series developed by our group, with increased selectivity and potency over "first generation" NOX inhibitors such as apocynin and DPI.CRITICAL ISSUES: The precise role of NOX enzymes in tumor biology remains poorly defined. The tumorigenic properties of NOXs vary with cancer type, and precise tools, such as selective inhibitors, are needed to deconvolute NOX contribution to cancer development. Most NOX inhibitors developed to date are unspecific and/or their mechanistic and pharmacological characteristics are not well defined. A lack of high-resolution crystal structures for NADPH oxidase functional domains has hindered the development of potent and selective inhibitors.
    FUTURE DIRECTIONS: In-depth studies of NOX interactions with the tumor microenvironment (e.g., cytokines, cell-surface antigens) will help identify new approaches for NOX inhibition in cancer.
    DOI:  https://doi.org/10.1089/ars.2020.8046
  2. Antioxid Redox Signal. 2020 Feb 01.
    Urner S, Ho F, Jha JC, Ziegler D, Jandeleit-Dahm K.
      SIGNIFICANCE: Oxidative stress plays a critical role in the development and progression of serious micro- and macrovascular complications of diabetes. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) significantly contribute to oxidative stress-associated inflammatory pathways that lead to tissue damage of different organs, including the kidneys, retina, brain, nerves and the cardiovascular system. Recent Advances: Pre-clinical studies, including genetic modified mouse models or cell culture models have revealed the role of specific NOX isoforms in different diabetic complications, and suggested them as a promising target for the treatment of these diseases. Critical Issues and Future Directions: In this review, we provide an overview of the role of ROS and oxidative stress in macrovascular complications, such as stroke, myocardial infarction, coronary artery disease and peripheral vascular disease that are all mainly driven by atherosclerosis, as well as microvascular complications, such as diabetic retinopathy, nephropathy and neuropathy. We summarize conducted genetic deletion studies of different Nox isoforms as well as pharmacological intervention studies using NOX inhibitors in the context of pre-clinical as well as clinical research on diabetic complications, and outline the isoforms that are most promising for future clinical trials.
    DOI:  https://doi.org/10.1089/ars.2020.8047
  3. Int J Biochem Cell Biol. 2020 Jan 31. pii: S1357-2725(20)30020-0. [Epub ahead of print] 105703
    Zhang Y, Ding H, Song Q, Wang Z, Yuan W, Ren Y, Zhao Z, Wang C.
      The renin-angiotensin system contributes to the pathogenesis of rheumatoid arthritis, but that the mechanism is unclear. This study aims to investigate the effect of angiotensin II (Ang II) on osteogenic differentiation of synoviocytes and the underlying mechanism. Ang II was showed to inhibite osteogenic differentiation of synoviocytes, which was mitigated by a Dickkopf-1 (DKK-1) inhibitor. DKK-1 was upregulated by Ang II, which was weakened by the Ang II type 1 receptor (AT1R) blocker, reactive oxygen species (ROS) scavenger, and p38 inhibitor. Ang II increased the levels of AT1R, ROS, and NADPH oxidase (NOX), and the upregulations were mitigated by the AT1R blocker or NOX inhibitor. Furthermore, Ang II activated the p38 pathway, which was blocked by the AT1R blocker, ROS scavenger, or siRNA-MKK3. In brief, these results indicate that Ang II upregulates NOX expression and ROS production via AT1R, activates the MKK3/p38 signaling, and in turn upregulates DKK-1 expression, participating in the inhibition of osteogenic differentiation of synoviocytes.
    Keywords:  Angiotensin II; Dickkopf-1; osteogenic differentiation; p38 pathway; synoviocytes
    DOI:  https://doi.org/10.1016/j.biocel.2020.105703
  4. Int J Mol Sci. 2020 Feb 03. pii: E1001. [Epub ahead of print]21(3):
    Lee HS, Park HY, Kwon SP, Kim B, Lee Y, Kim S, Shin KO, Park K.
      Human epidermis is positioned at the interface with the external environment, protecting our bodies against external challenges, including air pollutants. Emerging evidence suggests that diesel particulate extract (DPE), a major component of air pollution, leads to impairment of diverse cellular functions in keratinocytes (KC). In this study, we investigated the cellular mechanism underlying DPE-induced KC apoptosis. We first addressed cell death occurring in KC exposed to DPE, paralleled by increased activation of NADPH oxidases (NOXs) and subsequent ROS generation. Blockade of NOX activation with a specific inhibitor attenuated the expected DPE-induced KC apoptosis. In contrast, pre-treatment with a specific inhibitor of reactive oxygen species (ROS) generation did not reverse DPE/NOX-mediated increase in KC apoptosis. We next noted that NOX-mediated KC apoptosis is mainly attributable to neutral sphingomyelinase (SMase)-mediated stimulation of ceramides, which is a well-known pro-apoptotic lipid. Moreover, we found that inhibition of NOX activation significantly attenuated DPE-mediated increase in the ratio of ceramide to its key metabolite sphingosine-1-phosphate (S1P), an important determinant of cell fate. Together, these results suggest that activation of neutral SMase serves as a key downstream signal for the DPE/NOX activation-mediated alteration in ceramide and S1P productions, and subsequent KC apoptosis.
    Keywords:  NADPH oxidase; ceramide; diesel particulate extract; keratinocyte apoptosis; neutral sphingomyelinase
    DOI:  https://doi.org/10.3390/ijms21031001
  5. Cell Div. 2020 ;15 2
    Liu C, Liu L, Yang M, Li B, Yi J, Ai X, Zhang Y, Huang B, Li C, Feng C, Zhou Y.
      Background: The senescence of nucleus pulposus (NP) cells plays a vital role in the pathogenesis of intervertebral disc (IVD) degeneration (IDD). NADPH oxidase 4 (NOX4)-associated oxidative stress has been shown to induce premature NP cell senescence. Enhancer of zeste homolog 2 (EZH2) is a crucial gene regulating cell senescence. The aim of this study was to investigate the roles of EZH2 in NOX4-induced NP cell senescence and a feedback loop between EZH2 and NOX4.Results: The down-regulation of EZH2 and the up-regulation of NOX4 and p16 were observed in the degenerative discs of aging rats. EZH2 regulated NP cell senescence via the H3K27me3-p16 pathway. Also, EZH2 regulated the expression of NOX4 in NP cells through the histone H3 lysine 27 trimethylation (H3K27me3) in the promoter of NOX4 gene. Furthermore, NOX4 down-regulated EZH2 expression in NP cells via the canonical Wnt/β-catenin pathway.
    Conclusions: A positive feedback loop between EZH2 and NOX4 is involved in regulating NP cell senescence, which provides a novel insight into the mechanism of IDD and a potential therapeutic target for IDD.
    Keywords:  Epigenetic histone modification; Intervertebral disc degeneration; Nucleus pulposus cell senescence; Wnt/β-catenin signaling pathway
    DOI:  https://doi.org/10.1186/s13008-020-0060-x
  6. Med Sci Monit. 2020 Feb 03. 26 e919399
    Li Y, Li Y, Zheng S.
      BACKGROUND The aim of this study was to explore the effects of NADPH oxidase 5 (NOX5) in high glucose-stimulated human glomerular mesangial cells (HMCs). MATERIAL AND METHODS Cells were cultured under normal glucose (NG) or high glucose (HG) conditions. Then, NOX5 siRNA was transfected into HG-treated HMCs. A Cell Counting Kit-8 assay, colony formation assay and 5-ethynyl-20-deoxyuridine (EDU) incorporation assay were applied to measure cell proliferative ability. In addition, the levels of oxidative stress factors including reactive oxygen species (ROS), malonaldehyde (MDA), NADPH, superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX), inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-1ß, and monocyte chemoattractant protein-1 (MCP-1) in HMCs were detected by kits. Moreover, the expression of TLR4/NF-kappaB signaling and extracellular matrix (ECM) associated genes were evaluated by western blotting. RESULTS The results revealed that the NOX5 was overexpressed in HG-treated HMCs. Silencing of NOX5 decreased proliferation of HMCs induced by HG. And NOX5 silencing alleviated the production of MDA and NADPH accompanied by an increase of SOD and GSH-PX levels. Additionally, the contents of TNF-alpha, IL-6, IL-1ß, and MCP-1 were reduced after transfection with NOX5 siRNA. Furthermore, silencing of NOX5 deceased the expression of collagen I, collagen IV, TGF-ß1, and fibronectin induced by HG stimulation. TLR4, MyD88, and phospho-NF-kappaB p65 expression were downregulated notably in NOX5 silencing group. CONCLUSIONS Taken together, these findings demonstrated that inhibition of NOX5 attenuated HG-induced HMCs oxidative stress, inflammation, and ECM accumulation, suggesting that NOX5 may serve as a potential therapeutic target for diabetic nephropathy (DN) treatment.
    DOI:  https://doi.org/10.12659/MSM.919399
  7. J Immunol. 2020 Feb 05. pii: ji1900953. [Epub ahead of print]
    Kralova J, Drobek A, Prochazka J, Spoutil F, Fabisik M, Glatzova D, Borna S, Pokorna J, Skopcova T, Angelisova P, Gregor M, Kovarik P, Sedlacek R, Brdicka T.
      Autoinflammatory diseases are characterized by dysregulation of the innate immune system, leading to spontaneous inflammation. Pstpip2cmo mouse strain is a well-characterized model of this class of disorders. Because of the mutation leading to the lack of adaptor protein PSTPIP2, these animals suffer from autoinflammatory chronic multifocal osteomyelitis similar to several human syndromes. Current evidence suggests that it is driven by hyperproduction of IL-1β by neutrophil granulocytes. In this study, we show that in addition to IL-1β, PSTPIP2 also negatively regulates pathways governing reactive oxygen species generation by neutrophil NOX2 NADPH oxidase. Pstpip2cmo neutrophils display highly elevated superoxide production in response to a range of stimuli. Inactivation of NOX2 NADPH oxidase in Pstpip2cmo mice did not affect IL-1β levels, and the autoinflammatory process was initiated with similar kinetics. However, the bone destruction was almost completely alleviated, suggesting that dysregulated NADPH oxidase activity is a key factor promoting autoinflammatory bone damage in Pstpip2cmo mice.
    DOI:  https://doi.org/10.4049/jimmunol.1900953
  8. Drug Des Devel Ther. 2020 ;14 145-155
    Wang Z, Tang T, Wang S, Cai T, Tao H, Zhang Q, Qi S, Qi Z.
      Background: Aloin has been reported to have many pharmacological effects including anti-inflammatory, anti-oxidant and anti-tumour activities. However, the precise molecular mechanisms underlying the anti-tumour properties of aloin are yet to be elucidated.Methods: HGC-27 and BGC-823 gastric cancer cells were treated with aloin. EdU and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using wound healing and transwell assays. Western blotting was used to detect the levels of cyclinD1, cyclin E1, MMPs, N-cadherin, E-cadherin and NOX2. The phosphorylation of Akt, mTOR, P70S6K, S6, Src, stat3 and IκBα were also detected by Western blotting. Flow cytometry was used to detect the cell cycle distribution.The location of p65 in cells was determined by using a confocal microscopy assay. The total amounts of ROS present in cells were measured using an ROS assay kit.
    Results: Here, we found that aloin inhibited the proliferation and migration of HGC-27 and BGC-823 gastric cancer cells using a combination of EdU, colony formation, wound healing and transwell assays. Further investigations revealed that aloin decreased the protein expression levels of cyclin D1, N-cadherin, and the matrix metalloproteinases (MMP)-2 and MMP-9; increased E-cadherin expression in a dose-dependent manner; inhibited reactive oxygen species (ROS) generation; and mediated the activation of Akt-mTOR, signal transducer and activator of transcription-3 (Stat3), and NF-κB signalling pathways. Our results also indicated that aloin is able to attenuate the expression levels of the two regulatory proteins of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), p47phox and p22phox, but had no effect on the level of gp91phox. N-acetylcysteine treatment of gastric cancer cells inhibited ROS production and Akt-mTOR, Stat3, and IκBα phosphorylation. Taken together, our data suggest that aloin inhibits the proliferation and migration of gastric cancer cells by downregulating NOX2-ROS-mediated activation of the Akt-mTOR, Stat3, and NF-κB signalling pathways.
    Conclusion: Our findings suggest a potential role for aloin in the prevention of gastric cancer cell proliferation and migration and provide novel insights into the anti-cancer properties of aloin.
    Keywords:  aloin; gastric cancer; migration; nicotinamide adenine dinucleotide phosphate oxidase 2; proliferation; reactive oxygen species
    DOI:  https://doi.org/10.2147/DDDT.S219247
  9. Biochem Biophys Res Commun. 2020 Feb 01. pii: S0006-291X(20)30217-5. [Epub ahead of print]
    Li D, Cong Z, Yang C, Zhu X.
      Inhibiting the production of reactive oxygen species (ROS) in alveolar epithelial cells (AECs) under oxidative distress becomes a new therapeutic strategy for acute respiratory distress syndrome (ARDS). Herein in the present study, we investigated effects of Nox2, the catalytic subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase type 2, on LPS-induced epithelium injury in ARDS mice and in human alveolar epithelial A549 cells. Severe lung injury, disruption of alveolar-capillary barrier with the loss of zonula occluden (ZO)-1 and up-regulated expression of Nox2 in AECs were exhibited in ARDS mice. In vitro, LPS induced decreased cell viability coupled with activated Nox2, high level of ROS, and destroyed ZO-1 distribution. Moreover, VAS2870 proved to inhibit Nox2 expression, reduce ROS generation, restore epithelium barrier integrity, and preserve cell viability in LPS-induced A549 cells. These data demonstrate that Nox2/ROS/ZO-1 axis is of great importance in AECs damage induced by LPS, and the utilization of VAS2870 to inhibit this pathway might lighten LPS-induced ARDS.
    Keywords:  ARDS; Alveolar epithelial cell; LPS; Nox2; Tight junctions
    DOI:  https://doi.org/10.1016/j.bbrc.2020.01.134
  10. Antioxid Redox Signal. 2020 Feb 01.
    Erlich J, To E, Liong S, Brooks RD, Vlahos R, O'Leary JJ, Brooks DA, Selemidis S.
      SIGNIFICANCE: Up until recently, metabolism has scarcely been referenced in terms of immunology. However, emerging evidence has shown that immune cells undergo an adaptation of metabolic processes, known as the metabolic switch. This switch is key to the activation, and sustained inflammatory phenotype in immune cells, which includes the production of cytokines and reactive oxygen species (ROS) that underpin infectious diseases, respiratory and cardiovascular disease, neurodegenerative disease as well as cancer. Recent Advances: There is a burgeoning body of evidence that immunometabolism and redox biology drive infectious diseases. For example, influenza A virus (IAV) utilise endogenous ROS production via NOX2-containing NADPH oxidases and mitochondria to circumvent antiviral responses. These evolutionary conserved processes are promoted by glycolysis, the pentose phosphate pathway and the tricarboxylic acid cycle that drive inflammation. Such metabolic products involve succinate, which stimulates inflammation through ROS-dependent stabilisation of HIF-1α, promoting IL-1β production by the inflammasome. In addition, itaconate has recently gained significant attention for its role as an anti-inflammatory and antioxidant metabolite of the TCA cycle. Critical Issues and Future directions: The molecular mechanisms by which immunometabolism and ROS promote viral and bacterial pathology are largely unknown. This review will provide an overview of the current paradigms with an emphasis on the roles of immunometabolism and ROS in the context of IAV infection and secondary complications due to bacterial infection such as streptococcus pneumoniae. Molecular targets based on metabolic cell processes and ROS generation may provide novel and effective therapeutic strategies for IAV and associated bacterial superinfections.
    DOI:  https://doi.org/10.1089/ars.2020.8028