bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2020‒02‒16
six papers selected by
Laia Caja Puigsubira
Uppsala University

  1. BMJ Open Diabetes Res Care. 2020 Feb;pii: e000951. [Epub ahead of print]8(1):
    Pang H, Li J, Du H, Gao Y, Lv J, Liu Y, Li SJ.
      OBJECTIVE: The voltage-gated proton channel Hv1 has been proposed to mediate NADPH oxidase (NOX) function by regulating intracellular pH during respiratory bursts. In our previous work, we showed that Hv1 is expressed in pancreatic β cells and positively regulates insulin secretion. Here, we investigated the role of Hv1 in adipose tissue differentiation, metabolic homeostasis and insulin sensitivity using Hv1 knockout (KO) mice.DESIGN: Mice with genetic deletion of Hv1 are treated with high-fat diet (HFD) similar to wild-type (WT) mice. Body weight gain, adiposity, insulin sensitivity and gene expressions in both adipose tissue and liver were analyzed.
    RESULTS: Mice with genetic deletion of Hv1 display overt obesity with higher body weight gain and accumulation of adipose tissue compared with similarly HFD-treated WT. Hv1-deficient mice develop more glucose intolerance than WT, but no significant difference in insulin resistance, after fed with HFD. Deficiency of Hv1 results in a remarkable increase in epididymal adipocyte weight and size, while the gene expressions of proinflammatory factors and cytokines are obviously enhanced in the HFD-fed mice. Furthermore, the gene expression of Hv1 is increased in the HFD-fed mice, which is accompanied by the increase of NOX2 and NOX4. In addition, there is more severely diet-induced steatosis and inflammation in liver in KO mice.
    CONCLUSION: Our data demonstrated that lacking of Hv1 results in diet-induced obesity in mice through inflammation and hepatic steatosis. This study suggested that Hv1 acts as a positive regulator of metabolic homeostasis and a potential target for antiobesity drugs in therapy and may serve as an adaptive mechanism in cooperating with NOX to mediate reactive oxygen species for adipogenesis and insulin sensitivity.
    Keywords:  adipogenesis; hepatic steatosis; inflammation; obesity
  2. J Diabetes Res. 2020 ;2020 2521590
    Qi J, Luo X, Ma Z, Zhang B, Li S, Duan X, Yang B, Zhang J.
      Nonpharmaceutical therapies such as exercise training and diet intervention are widely used for the treatment of insulin resistance (IR). Although the skeletal muscle is the major peripheral tissue of glucose metabolism under insulin stimulation, the mechanism underlying muscle IR is poorly understood. Using a high-fat diet-induced IR mouse model, we here show that NADPH oxidase 4 (Nox4) upregulation mediates the production of reactive oxygen species (ROS) that causes metabolic syndrome featuring IR. The Nox4 expression level was markedly elevated in IR mice, and Nox4 overexpression was sufficient to trigger IR. Conversely, downregulation of Nox4 expression through exercise training prevented diet-induced IR by reducing the production of ROS and enhancing the AKT signaling pathway. Thus, this study indicates that exercise might improve IR through a reduction of Nox4-induced ROS in the skeletal muscle and enhancement of AKT signal transduction.
  3. Int Forum Allergy Rhinol. 2020 Feb 13.
    Zheng K, Hao J, Xiao L, Wang M, Zhao Y, Fan D, Li Y, Wang X, Zhang L.
      BACKGROUND: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces reactive oxygen species (ROS) involved in oxidative stress and signal transduction. Recent studies have suggested that NADPH oxidase is associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). The aim of this study was to detect the expression of NADPH oxidase subunits and 4-hydroxynonenal (4-HNE) in nasal polyp tissue and normal nasal mucosa, in order to explore the possible role played by NADPH oxidase in the pathogenesis of CRSwNP.METHODS: Thirteen patients with CRSwNP and 9 normal control subjects were selected to participate in this study, in which we evaluated the expression of different NADPH oxidase subunits (gp91phox , p67phox , p47phox , and p22phox ) in nasal polyp (NP) tissue and control mucosa by Western blotting and real-time polymerase chain reaction (PCR). Immunohistochemistry and immunofluorescence staining were used to detect expression of the p67phox subunit and 4-HNE in NP tissue and normal nasal mucosa.
    RESULTS: Western blot and real-time PCR results showed that p67phox expression was significantly increased in NP tissue when compared with its expression in control mucosa (p = 0.004). p67phox was expressed in the eosinophils and neutrophils found in NP tissue, but not in the macrophages. Additionally, the levels of 4-HNE expression were also significantly increased in NP tissue when compared with control mucosa (p = 0.001).
    CONCLUSION: The levels of p67phox messenger RNA (mRNA) and protein as well as 4-HNE were both upregulated in NP tissue, suggesting that p67phox and oxidative stress play roles in the pathogenesis of CRSwNP.
    Keywords:  4-HNE; NADPH oxidase; Western blot; chronic rhinosinusitis; gp91phox; p22phox; p47phox; p67phox; real-time PCR
  4. JACC Basic Transl Sci. 2020 Jan;5(1): 35-49
    Liu H, Wang L, Pan Y, Wang X, Ding Y, Zhou C, Shah AM, Zhao G, Zhang M.
      This study sought to investigate whether reactive oxygen species (ROS)-generating reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2) contributes to calcific aortic valve disease (CAVD) or whether celastrol, a natural Nox2 inhibitor, may provide potential therapeutic target for CAVD. CAVD is an active and cellular-driven fibrocalcific process characterized by differentiation of aortic valvular interstitial cells (AVICs) toward an osteogenic-like phenotype. ROS levels increase in calcified aortic valves, while the sources of ROS and their roles in the pathogenesis of CAVD are elusive. The roles of Nox2 and the effects of celastrol were studied using cultured porcine AVICs in vitro and a rabbit CAVD model in vivo. Nox2 proteins were significantly upregulated in human aortic valves with CAVD. In vitro, Nox2 was markedly induced upon stimulation of AVICs with osteogenic medium, along with the increases in ROS production and calcium nodule formation. Celastrol significantly decreased calcium deposition of AVICs by 35%, with a reduction of ROS generation. Knockdown of endogenous Nox2 substantially suppressed AVIC calcification by 39%, the inhibitory effect being similar to celastrol treatment. Mechanistically, either celastrol treatment or knockdown of Nox2 significantly inhibited glycogen synthase kinase 3 beta/β-catenin signaling, leading to attenuation of fibrogenic and osteogenic responses of AVICs. In a rabbit CAVD model, administration of celastrol significantly reduced aortic valve ROS production, fibrosis, calcification, and severity of aortic stenosis, with less left ventricular dilatation and better preserved contractile function. Upregulation of Nox2 is critically involved in CAVD. Celastrol is effective to alleviate CAVD, likely through the inhibition of Nox2-mediated glycogen synthase kinase 3 beta/β-catenin pathway in AVICs.
    Keywords:  AV, aortic valve; AVIC, aortic valvular interstitial cell; CAVD, calcific aortic valve disease; GSK3B, glycogen synthase kinase 3 beta; HC, high cholesterol; LV, left ventricular; Nox2; Nox2, reduced nicotinamide adenine dinucleotide phosphate oxidase 2; OGM, osteogenic medium; OPN, osteopontin; ROS, reactive oxygen species; Runx2, runt-related transcription factor 2; fibrosis; reactive oxygen species; stenosis; tripterine; valve interstitial cells; vitD2, vitamin D2
  5. Cells. 2020 Feb 12. pii: E432. [Epub ahead of print]9(2):
    Delierneux C, Kouba S, Shanmughapriya S, Potier-Cartereau M, Trebak M, Hempel N.
      Calcium (Ca2+) uptake into the mitochondria shapes cellular Ca2+ signals and acts as a key effector for ATP generation. In addition, mitochondria-derived reactive oxygen species (mROS), produced as a consequence of ATP synthesis at the electron transport chain (ETC), modulate cellular signaling pathways that contribute to many cellular processes. Cancer cells modulate mitochondrial Ca2+ ([Ca2+]m) homeostasis by altering the expression and function of mitochondrial Ca2+ channels and transporters required for the uptake and extrusion of mitochondrial Ca2+. Regulated elevations in [Ca2+]m are required for the activity of several mitochondrial enzymes, and this in turn regulates metabolic flux, mitochondrial ETC function and mROS generation. Alterations in both [Ca2+]m and mROS are hallmarks of many tumors, and elevated mROS is a known driver of pro-tumorigenic redox signaling, resulting in the activation of pathways implicated in cellular proliferation, metabolic alterations and stress-adaptations. In this review, we highlight recent studies that demonstrate the interplay between [Ca2+]m and mROS signaling in cancer.
    Keywords:  ROS; cancer; mitochondrial Ca2+ transport; mitochondrial ROS; redox signaling
  6. Cancer Res. 2020 Feb 10. pii: canres.3094.2019. [Epub ahead of print]
    Gibson AR, O'Leary BR, Du J, Sarsour EH, Kalen AL, Wagner BA, Stolwijk JM, Falls-Hubert KC, Alexander MS, Carroll RS, Spitz DR, Buettner GR, Goswami PC, Cullen JJ.
      Pharmacological ascorbate treatment (P-AscH-, high-dose, intravenous vitamin C) results in a transient short-term increase in the flux of hydrogen peroxide that is preferentially cytotoxic to cancer cells vs. normal cells. This study examines whether an increase in hydrogen peroxide is sustained post-treatment and potential mechanisms involved in this process. Cellular bioenergetic profiling following treatment with P-AscH- was examined in tumorigenic and non-tumorigenic cells. P-AscH- resulted in sustained increases in the rate of cellular oxygen consumption (OCR) and reactive oxygen species (ROS) in tumor cells with no changes in non-tumorigenic cells. Sources for this increase in ROS and OCR were DUOX 1 and 2, which are silenced in PDAC, but upregulated with P-AscH- treatment. An inducible catalase system, to test causality for the role of hydrogen peroxide, reversed the P-AscH--induced increases in DUOX, while DUOX inhibition partially rescued P-AscH--induced toxicity. In addition, DUOX was significantly downregulated in pancreatic cancer specimens compared to normal pancreas tissues. Together these results suggest that P-AscH--induced toxicity may be enhanced by late metabolic shifts in tumor cells resulting in a feed-forward mechanism for generation of hydrogen peroxide and induction of metabolic stress through enhanced DUOX expression and rate of oxygen consumption.