bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2019‒08‒11
six papers selected by
Laia Caja Puigsubira
Uppsala University


  1. Cardiovasc Res. 2019 Aug 08. pii: cvz213. [Epub ahead of print]
    Hahner F, Moll F, Schröder K.
      The differentiation of stem cells into endothelial cells involves the modulation of highly interconnected metabolic and epigenetic processes. Therefore, the differentiation of endothelial cells is a tightly controlled process, which is adjusted at multiple levels, meaning that even the smallest variation can result in major consequences. Reactive oxygen species (ROS) represent a group of second messengers that can interfere with both metabolic and epigenetic processes. Besides their generation by mitochondria, ROS are produced in a controlled manner by the family of NADPH oxidases. The different members of the NADPH oxidase family produce superoxide anions or hydrogen peroxide. Due to the specific sub-cellular localization of the different NADPH oxidases, ROS are produced at diverse sites in the cell, such as the plasma membrane or the endoplasmic reticulum. Once produced, ROS interfere with proteins, lipids and DNA to modulate intracellular signal cascades. Accordingly, ROS represent a group of readily available and specifically localized modulators of the highly sophisticated signaling network that eventually leads to the differentiation of stem cells into endothelial cells. This review focusses on the role of NADPH oxidases in the differentiation of stem cells into endothelial cells.
    Keywords:  NADPH oxidase; differentiation; endothelial cells; reactive oxygen species
    DOI:  https://doi.org/10.1093/cvr/cvz213
  2. Redox Biol. 2019 Jul 19. pii: S2213-2317(19)30673-1. [Epub ahead of print]26 101278
    Shekh-Ahmad T, Lieb A, Kovac S, Gola L, Wigley WC, Abramov AY, Walker MC.
      Many epilepsies are acquired conditions following an insult to the brain such as a prolonged seizure, traumatic brain injury or stroke. The generation of reactive oxygen species (ROS) and induction of oxidative stress are common sequelae of such brain insults and have been shown to contribute to neuronal death and the development of epilepsy. Here, we show that combination therapy targeting the generation of ROS through NADPH oxidase inhibition and the endogenous antioxidant system through nuclear factor erythroid 2-related factor 2 (Nrf2) activation prevents excessive ROS accumulation, mitochondrial depolarisation and neuronal death during in vitro seizure-like activity. Moreover, this combination therapy prevented the development of spontaneous seizures in 40% of animals following status epilepticus (70% of animals were seizure free after 8 weeks) and modified the severity of epilepsy when given to chronic epileptic animals.
    Keywords:  Epileptogenesis; Keap1-Nrf2 pathway; NADPH oxidase; Oxidative stress; Spontaneous seizures
    DOI:  https://doi.org/10.1016/j.redox.2019.101278
  3. Oncogenesis. 2019 Aug 06. 8(8): 40
    Wu JR, You RI, Hu CT, Cheng CC, Rudy R, Wu WS.
      Target therapy aiming at critical molecules within the metastatic signal pathways is essential for prevention of hepatocellular carcinoma (HCC) progression. Hic-5 (hydrogen peroxide inducible clone-5) which belongs to the paxillin superfamily, can be stimulated by a lot of metastatic factors, such as transforming growth factor (TGF-β), hepatocyte growth factor (HGF), and reactive oxygen species (ROS). Previous studies implicated Hic-5 cross-talks with the ROS-c-jun N-terminal kinase (JNK) signal cascade in a positive feedback manner. In this report, we addressed this issue in a comprehensive manner. By RNA interference and ectopic Hic-5 expression, we demonstrated Hic-5 was essential for activation of NADPH oxidase and ROS generation leading to activation of downstream JNK and c-jun transcription factor. This was initiated by interaction of Hic-5 with the regulator and adaptor of NADPH oxidase, Rac1 and Traf4, respectively, which may further phosphorylate the nonreceptor tyrosine kinase Pyk2 at Tyr881. On the other hand, promoter activity assay coupled with deletion mapping and site directed mutagenesis strategies demonstrated the distal c-jun and AP4 putative binding regions (943-1126 bp upstream of translational start site) were required for transcriptional activation of Hic-5. Thus Hic-5 was both downstream and upstream of NADPH oxidase-ROS-JNK-c-jun cascade. This signal circuit was essential for regulating the expression of epithelial mesenchymal transition (EMT) factors, such as Snail, Zeb1, E-cadherin, and matrix metalloproteinase 9, involved in HCC cell migration and metastasis. Due to the limited expression of Hic-5 in normal tissue, it can be a promising therapeutic target for preventing HCC metastasis.
    DOI:  https://doi.org/10.1038/s41389-019-0149-8
  4. Radiat Oncol. 2019 Aug 09. 14(1): 142
    Lacombe J, Brengues M, Mangé A, Bourgier C, Gourgou S, Pèlegrin A, Ozsahin M, Solassol J, Azria D.
      BACKGROUND: Biomarkers for predicting late normal tissue toxicity to radiotherapy are necessary to personalize treatments and to optimize clinical benefit. Many radiogenomic studies have been published on this topic. Conversely, proteomics approaches are not much developed, despite their advantages.METHODS: We used the isobaric tags for relative and absolute quantitation (iTRAQ) proteomic approach to analyze differences in protein expression levels in ex-vivo irradiated (8 Gy) T lymphocytes from patients with grade ≥ 2 radiation-induced breast fibrosis (grade ≥ 2 bf+) and patients with grade < 2 bf + after curative intent radiotherapy. Patients were selected from two prospective clinical trials (COHORT and PHRC 2005) and were used as discovery and confirmation cohorts.
    RESULTS: Among the 1979 quantified proteins, 23 fulfilled our stringent biological criteria. Immunoblotting analysis of four of these candidate proteins (adenylate kinase 2, AK2; annexin A1; heat shock cognate 71 kDa protein; and isocitrate dehydrogenase 2) confirmed AK2 overexpression in 8 Gy-irradiated T lymphocytes from patients with grade ≥ 2 bf + compared with patients with grade < 2 bf+. As these candidate proteins are involved in oxidative stress regulation, we also evaluated radiation-induced reactive oxygen species (ROS) production in peripheral blood mononuclear cells from patients with grade ≥ 2 bf + and grade < 2 bf+. Total ROS level, and especially superoxide anion level, increased upon ex-vivo 8 Gy-irradiation in all patients. Analysis of NADPH oxidases (NOXs), a major source of superoxide ion in the cell, showed a significant increase of NOX4 mRNA and protein levels after irradiation in both patient groups. Conversely, only NOX4 mRNA level was significantly different between groups (grade ≥ 2 bf + and grade < 2 bf+).
    CONCLUSION: These findings identify AK2 as a potential radiosensitivity candidate biomarker. Overall, our proteomic approach highlights the important role of oxidative stress in late radiation-induced toxicity, and paves the way for additional studies on NOXs and superoxide ion metabolism.
    Keywords:  AK2; NADPH oxidases; Normal tissue radiotoxicity; Proteomics; Radiation-induced breast fibrosis; Radiosensitivity; Radiotherapy
    DOI:  https://doi.org/10.1186/s13014-019-1351-8
  5. Antioxidants (Basel). 2019 Aug 06. pii: E281. [Epub ahead of print]8(8):
    Caruso G, Fresta CG, Fidilio A, O'Donnell F, Musso N, Lazzarino G, Grasso M, Amorini AM, Tascedda F, Bucolo C, Drago F, Tavazzi B, Lazzarino G, Lunte SM, Caraci F.
      Carnosine is an endogenous dipeptide composed of β-alanine and L-histidine. This naturally occurring molecule is present at high concentrations in several mammalian excitable tissues such as muscles and brain, while it can be found at low concentrations in a few invertebrates. Carnosine has been shown to be involved in different cellular defense mechanisms including the inhibition of protein cross-linking, reactive oxygen and nitrogen species detoxification as well as the counteraction of inflammation. As a part of the immune response, macrophages are the primary cell type that is activated. These cells play a crucial role in many diseases associated with oxidative stress and inflammation, including atherosclerosis, diabetes, and neurodegenerative diseases. In the present study, carnosine was first tested for its ability to counteract oxidative stress. In our experimental model, represented by RAW 264.7 macrophages challenged with phorbol 12-myristate 13-acetate (PMA) and superoxide dismutase (SOD) inhibitors, carnosine was able to decrease the intracellular concentration of superoxide anions (O2-•) as well as the expression of Nox1 and Nox2 enzyme genes. This carnosine antioxidant activity was accompanied by the attenuation of the PMA-induced Akt phosphorylation, the down-regulation of TNF-α and IL-6 mRNAs, and the up-regulation of the expression of the anti-inflammatory mediators IL-4, IL-10, and TGF-β1. Additionally, when carnosine was used at the highest dose (20 mM), there was a generalized amelioration of the macrophage energy state, evaluated through the increase both in the total nucleoside triphosphate concentrations and the sum of the pool of intracellular nicotinic coenzymes. Finally, carnosine was able to decrease the oxidized (NADP+)/reduced (NADPH) ratio of nicotinamide adenine dinucleotide phosphate in a concentration dependent manner, indicating a strong inhibitory effect of this molecule towards the main source of reactive oxygen species in macrophages. Our data suggest a multimodal mechanism of action of carnosine underlying its beneficial effects on macrophage cells under oxidative stress and inflammation conditions.
    Keywords:  antioxidants; carnosine; inflammation; macrophages; oxidative stress; superoxide
    DOI:  https://doi.org/10.3390/antiox8080281
  6. Am J Physiol Gastrointest Liver Physiol. 2019 Aug 08.
    Al-Badrani M, Seth RK, Sarkar S, Kimono D, Mondal A, Bose D, Porter DE, Scott GI, Brooks B, Raychoudhury S, Nagarkatti M, Nagarkatti PS, Jule Y, Diehl AM, Chatterjee S.
      Nonalcoholic fatty liver disease (NAFLD)is an emerging global pandemic.. Though significant progress has been made in unraveling the pathophysiology of the disease, the role of protein phosphatase 2A (PP2A) and its subsequent inhibition by environmental and genetic factors in NAFLD pathophysiology remains unclear. The present report tests the hypothesis that an exogenous PP2A inhibitor leads to hepatic inflammation and fibrogenesis via NOX2 dependent pathway in NAFLD. Results showed that microcystin (MC) administration, a potent PP2A inhibitor found in environmental exposure led to an exacerbation of NAFLD pathology with increased CD68 immunoreactivity, the release of proinflammatory cytokines and stellate cell activation, a process that was attenuated in mice that lacked the p47 phox gene and miR21 knockout mice. Mechanistically, leptin primed-immortalized Kupffer cells(a mimicked model for a NAFLD condition), treated with apocynin or nitrone spin trap DMPO had significantly decreased CD68, decreased miR21 and α-SMA levels suggesting the role of NOX2-dependent reactive oxygen species in miR21-induced Kupffer cell activation and stellate cell pathology. Further, NOX2 dependent peroxynitrite generation was primarily responsible for cellular events observed following MC exposure since incubation with phenylboronic acid attenuated miR21 levels, Kupffer cell activation, and inflammatory cytokine release. Furthermore, blocking of AKT pathway attenuated PP2A-inhibitor-induced NOX2 activation and miR21 upregulation.Taken together, we show that PP2A may have protective roles and its inhibition exacerbates NAFLD pathology via activating NOX2 dependent peroxynitrite generation thus increasing miR21-induced pathology.
    Keywords:  Leptin; Microcystin; NADPH; PP2A inhibitor; peroxynitrite
    DOI:  https://doi.org/10.1152/ajpgi.00061.2019