bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2022–02–20
six papers selected by
Laia Caja Puigsubira, Uppsala University
  1. Oxidative Injury in Ischemic Stroke: A Focus on NADPH Oxidase 4.
  2. The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of acute myeloid leukemias.
  3. Outgrowth endothelial progenitor cells restore cerebral barrier function following ischaemic damage: the impact of NOX2 inhibition.
  4. NOX2-Induced High Glycolytic Activity Contributes to the Gain of COL5A1-Mediated Mesenchymal Phenotype in GBM.
  5. Exercise and nitrite prevent and Nω-nitrol-L-arginine methyl ester reproduces imbalance in the nuclear factor-κB/NADPH oxidase 2 and nuclear factor erythroid 2-related factor 2/NADPH oxidase 4/endothelial nitric oxide synthase systems in diabetes.
  6. Role of CD133/NRF2 Axis in the Development of Colon Cancer Stem Cell-Like Properties.
  1. Oxid Med Cell Longev. 2022 ;2022 1148874
    Oxidative Injury in Ischemic Stroke: A Focus on NADPH Oxidase 4.
    Ganglei Li, Changsheng Ye, Yu Zhu, Tiesong Zhang, Jun Gu, Jianwei Pan, Feng Wang, Fan Wu, Kaiyuan Huang, Kangli Xu, Xiaomin Wu, Jian Shen.
      Ischemic stroke is a leading cause of disability and mortality worldwide. Thus, it is urgent to explore its pathophysiological mechanisms and find new therapeutic strategies for its successful treatment. The relationship between oxidative stress and ischemic stroke is increasingly appreciated and attracting considerable attention. ROS serves as a source of oxidative stress. It is a byproduct of mitochondrial metabolism but primarily a functional product of NADPH oxidases (NOX) family members. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is most closely related to the formation of ROS during ischemic stroke. Its expression is significantly upregulated after cerebral ischemia, making it a promising target for treating ischemic stroke. Several drugs targeting NOX4, such as SCM-198, Iso, G-Rb1, betulinic acid, and electroacupuncture, have shown efficacy as treatments of ischemic stroke. MTfp-NOX4 POC provides a novel insight for the treatment of stroke. Combinations of these therapies also provide new approaches for the therapy of ischemic stroke. In this review, we summarize the subcellular location, expression, and pathophysiological mechanisms of NOX4 in the occurrence and development of ischemic stroke. We also discuss the therapeutic strategies and related regulatory mechanisms for treating ischemic stroke. We further comment on the shortcomings of current NOX4-targeted therapy studies and the direction for improvement.
    DOI:  https://doi.org/10.1155/2022/1148874
  2. Haematologica. 2022 Feb 17.
    The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of acute myeloid leukemias.
    Rosa Paolillo, Mathias Boulanger, Pierre Gâtel, Ludovic Gabellier, Marion De Toledo, Denis Tempé, Rawan Hallal, Dana Akl, Jérôme Moreaux, Hayeon Baik, Elise Gueret, Christian Recher, Jean-Emmanuel Sarry, Guillaume Cartron, Marc Piechaczyk, Guillaume Bossis.
      Resistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara-C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up-regulation of the NOX2 NAPDH oxidase subunit genes (CYBB, CYBA, NCF1, NCF2, NCF4 and RAC2). The ensuing increase in NADPH oxidase expression and ROS production, which is particularly strong in DNR-resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. Gp91phox (CYBB-encoded Nox2 catalytic sub-unit), was found more expressed and active in leukemic cells from the FAB M4/M5 subtypes patients compared to FAB M0-M2 ones. Moreover, its expression was increased at the surface of patient's chemotherapy resistant AML cells. Using a gene expression-based score we finally demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis in AML patients. The prognosis NOX score we defined is independent of the cytogenetic-based risk classification, FAB subtype, FLT3/NPM1 mutational status and age.
    DOI:  https://doi.org/10.3324/haematol.2021.279889
  3. Eur J Neurosci. 2022 Feb 18.
    Outgrowth endothelial progenitor cells restore cerebral barrier function following ischaemic damage: the impact of NOX2 inhibition.
    Mansour Alwjwaj, Rais Reskiawan A Kadir, Ulvi Bayraktutan.
      Disruption of blood-brain barrier (BBB), formed mainly by human brain microvascular endothelial cells (HBMECs), constitutes the major cause of mortality following ischaemic stroke. This study investigates whether OECs (outgrowth endothelial cells) can restore BBB integrity and function following ischaemic damage, and how inhibition of NOX2, a main source of vascular oxidative stress, affects the characteristics of BBB established with OECs and HBMECs in ischaemic settings. In vitro models of human BBB were constructed by co-culture of pericytes and astrocytes with either OECs or HBMECs before exposure to oxygen-glucose deprivation (OGD) alone or followed by reperfusion (OGD+R) in the absence or presence of NOX2 inhibitor, gp91ds-tat. The function and integrity of BBB were assessed by measurements of paracellular flux of sodium fluorescein (NaF) and transendothelial electrical resistance (TEER), respectively. Treatment with OECs during OGD+R effectively restored BBB integrity and function. Compared to HBMECs, OECs possessed lower NADPH oxidase activity, superoxide anion levels, and had greater total antioxidant capacity during OGD and OGD+R. Inhibition of NADPH oxidase during OGD and OGD+R restored the integrity and function of BBB established by HBMECs. This was evidenced by reductions in NADPH oxidase activity and superoxide anion levels. In contrast, treatment with gp91ds-tat aggravated ischaemic injury-induced BBB damage constructed by OECs. In conclusion, OECs are more resistant to ischaemic conditions and can effectively repair cerebral barrier following ischaemic damage. Suppression of oxidative stress through specific targeting of NOX2 requires close attention while using OECs as therapeutics.
    Keywords:  NADPH oxidase; NOX2; OECs; Outgrowth endothelial cells; Oxidative stress; blood-brain barrier; cell therapy; cytoskeleton; ischaemic stroke; reactive oxygen species
    DOI:  https://doi.org/10.1111/ejn.15627
  4. Cancers (Basel). 2022 Jan 20. pii: 516. [Epub ahead of print]14(3):
    NOX2-Induced High Glycolytic Activity Contributes to the Gain of COL5A1-Mediated Mesenchymal Phenotype in GBM.
    Youngjoon Park, Minwoo Park, Junhyung Kim, Juwon Ahn, Jeongmin Sim, Ji-In Bang, Jinhyung Heo, Hyejeong Choi, Kyunggi Cho, Mihye Lee, Jong-Seok Moon, Jaejoon Lim.
      The alteration of the cellular metabolism is a hallmark of glioma. The high glycolytic phenotype is a critical factor in the pathogenesis of high-grade glioma, including glioblastoma multiforme (GBM). GBM has been stratified into three subtypes as the proneural, mesenchymal, and classical subtypes. High glycolytic activity was found in mesenchymal GBM relative to proneural GBM. NADPH oxidase 2 (NOX2) has been linked to cellular metabolism and epithelial-mesenchymal transition (EMT) in tumors. The role of NOX2 in the regulation of the high glycolytic phenotype and the gain of the mesenchymal subtype in glioma remain unclear. Here, our results show that the levels of NOX2 were elevated in patients with GBM. NOX2 induces hexokinase 2 (HK2)-dependent high glycolytic activity in U87MG glioma cells. High levels of NOX2 are correlated with high levels of HK2 and glucose uptake in patients with GBM relative to benign glioma. Moreover, NOX2 increases the expression of mesenchymal-subtype-related genes, including COL5A1 and FN1 in U87MG glioma cells. High levels of NOX2 are correlated with high levels of COL5A1 and the accumulation of extracellular matrix (ECM) in patients with GBM relative to benign glioma. Furthermore, high levels of HK2 are correlated with high levels of COL5A1 in patients with GBM relative to benign glioma. Our results suggest that NOX2-induced high glycolytic activity contributes to the gain of the COL5A1-mediated mesenchymal phenotype in GBM.
    Keywords:  COL5A1; GBM; NOX2; glycolysis; mesenchymal phenotype
    DOI:  https://doi.org/10.3390/cancers14030516
  5. J Physiol Pharmacol. 2021 Oct;72(5):
    Exercise and nitrite prevent and Nω-nitrol-L-arginine methyl ester reproduces imbalance in the nuclear factor-κB/NADPH oxidase 2 and nuclear factor erythroid 2-related factor 2/NADPH oxidase 4/endothelial nitric oxide synthase systems in diabetes.
    A Gajos-Draus, M Duda, A Beresewicz.
      Diabetes-induced vasculopathies are linked to inflammation mediated by mutually inhibitory nuclear factor-kappaB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). NF-κB is activated by superoxide (O2 ˙-)- producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase homologues, including NADPH oxidase 2 (Nox2), and vice versa, with NF-κB inducing Nox2. Nrf2 is activated by H2O2-producing Nox4 and nitric oxide (NO), but also induces NADPH oxidase 4 (Nox4) and endothelial nitric oxide synthase (eNOS). The NF-κB/Nox2 system is upregulated and Nrf2/Nox4/eNOS is downregulated in diabetes. We hypothesized that this vascular-deleterious imbalance results from the reduced vascular NO signaling, and so may be prevented by exercise training and sodium nitrite (interventions known to replenish vascular NO), and be reproduced by nitric oxide synthase (NOS) inhibition. Streptozotocin diabetic rats were examined on days 4, 10, 49 and 84 of diabetes. From day 4 onwards, plasma nitrite was reduced while NF-κB nuclear accumulation in the heart and kidneys gradually increased, while Nrf2 decreased. In parallel, the cardiac expression of signatures of the NF-κB (inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), NADPH oxidase 2 Nox2) increased and of the Nrf2 (Nox4, eNOS, heme-oxygenase-1 (HO-1)) decreased. Exercise training and dietary nitrite prevented this phenotype in the 49-day diabetes model. 7-day treatment of non-diabetic rats with NOS inhibitor of Nω-nitro-L-arginine methyl ester (L-NAME) recapitulated the NF-κB/Nox2 and Nrf2/Nox4/eNOS imbalance, as seen in diabetic rats. Nitrite failed to prevent the changes induced by L-NAME. The coherence of changes in NF-κB, Nox2, Nrf2, Nox4 and eNOS under the various settings of this study aimed at modifying the vascular NO leads us to propose that NF-κB/Nox2 and Nrf2/Nox4/eNOS are two crosstalking functional subsystems of one larger regulatory network, with NOS-derived NO ensuring the balance between these subsystems, and thus preventing vascular oxidative stress, endothelial dysfunction and inflammation.
    DOI:  https://doi.org/10.26402/jpp.2021.5.03
  6. Front Oncol. 2021 ;11 808300
    Role of CD133/NRF2 Axis in the Development of Colon Cancer Stem Cell-Like Properties.
    Jimin Park, Seung Ki Kim, Steffanus Pranoto Hallis, Bo-Hyun Choi, Mi-Kyoung Kwak.
      Cancer stem cells (CSCs) exhibit intrinsic therapy/stress resistance, which often cause cancer recurrence after therapy. In this study, we investigated the potential relationship between the cluster of differentiation (CD)-133, a CSC marker of colon cancer, and nuclear factor erythroid 2-like 2 (NFE2L2; NRF2), a master transcription factor for the regulation of multiple antioxidant genes. In the first model of CSC, a sphere culture of the colorectal cell line HCT116, showed increased levels of CD133 and NRF2. Silencing of CD133 reduced the levels of CSC markers, such as Kruppel-like factor 4 (KLF4) and ATP-binding cassette subfamily G member 2 (ABCG2), and further suppressed the expression levels of NRF2 and its target genes. As a potential molecular link, CD133-mediated activation of phosphoinositide 3-kinase/serine-threonine kinase (PI3K/AKT) signaling appears to increase the NRF2 protein levels via phosphorylation and the consequent inhibition of glycogen synthase kinase (GSK)-3β. Additionally, NRF2-silenced HCT116 cells showed attenuated sphere formation capacity and reduced CSC markers expression, indicating the critical role of the NRF2 pathway in the development of CSC-like properties. As a second model of CSC, the CD133high cell population was isolated from HCT116 cells. CSC-like properties, including sphere formation, motility, migration, colony formation, and anticancer resistance, were enhanced in the CD133high population compared to CD133low HCT116 cells. Levels of NRF2, which were elevated in CD133high HCT116, were suppressed by CD133-silencing. In line with these, the analysis of The Cancer Genome Atlas (TCGA) database showed that high levels of CD133 expression are correlated with increased NRF2 signaling, and alterations in CD133 gene or expression are associated with unfavorable clinical outcome in colorectal carcinoma patients. These results indicate that the CD133/NRF2 axis contributes to the development of CSC-like properties in colon cancer cells, and that PI3K/AKT signaling activation is involved in CD133-mediated NRF2 activation.
    Keywords:  CD133; NRF2; PI3K/AKT/GSK-3β; cancer stem cell; colorectal cancer; sphere formation
    DOI:  https://doi.org/10.3389/fonc.2021.808300
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