bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2019‒07‒07
three papers selected by
Laia Caja Puigsubira
Uppsala University

  1. Antioxid Redox Signal. 2019 Jun 28.
    DeVallance E, Li Y, Jurczak M, Cifuentes-Pagano E, Pagano PJ.
      SIGNIFICANCE: Highly prevalent in Western cultures, obesity, metabolic syndrome, and diabetes increase the risk of cardiovascular morbidity and mortality and cost health care systems billions of dollars annually. At the cellular level, obesity, metabolic syndrome, and diabetes are associated with increased production of reactive oxygen species (ROS). Increased levels of ROS production in key organ systems like adipose tissue, skeletal muscle, and the vasculature causes disruption of tissue homeostasis leading to increased morbidity and risk of mortality. More specifically, growing evidence implicates the NADPH oxidase (Nox) enzymes in these pathologies through impairment of insulin signaling, inflammation, and vascular dysfunction. The Nox family of enzymes is a major driver of redox signaling through its production of superoxide anion, hydrogen peroxide and downstream oxidative metabolites.CRITICAL ISSUES: However, due to the short half-lives of individual ROS and/or cellular defense systems, radii of ROS diffusion are commonly short, restricting redox signaling and oxidant stress to often localized events. Thus, special emphasis should be placed on cell type and subcellular location of Nox enzymes to better understand their role in the pathophysiology of metabolic diseases. Recent Advances: The primary goal of this review is to highlight recent advances and survey our current understanding of cell specific Nox enzymes' contributions to metabolic diseases.
    FUTURE DIRECTIONS: We discuss the targeting of Nox enzymes as potential therapy and bring to light potential emerging areas Nox research, microparticles and epigenetics, in the context of metabolic disease.
  2. Redox Biol. 2019 Jun 05. pii: S2213-2317(19)30303-9. [Epub ahead of print]26 101234
    Rajaram RD, Dissard R, Faivre A, Ino F, Delitsikou V, Jaquet V, Cagarelli T, Lindenmeyer M, Jansen-Duerr P, Cohen C, Moll S, de Seigneux S.
      BACKGROUND: NADPH oxidase 4 (NOX4) catalyzes the formation of hydrogen peroxide (H2O2). NOX4 is highly expressed in the kidney, but its role in renal injury is unclear and may depend on its specific tissue localization.METHODS: We performed immunostaining with a specific anti-NOX4 antibody and measured NOX4 mRNA expression in human renal biopsies encompassing diverse renal diseases. We generated transgenic mice specifically overexpressing mouse Nox4 in renal tubular cells and subjected the animals to the unilateral ureteral obstruction (UUO) model of fibrosis.
    RESULTS: In normal human kidney, NOX4 protein expression was at its highest on the basolateral side of proximal tubular cells. NOX4 expression increased in mesangial cells and podocytes in proliferative diabetic nephropathy. In tubular cells, NOX4 protein expression decreased in all types of chronic renal disease studied. This finding was substantiated by decreased NOX4 mRNA expression in the tubulo-interstitial compartment in a repository of 175 human renal biopsies. Overexpression of tubular NOX4 in mice resulted in enhanced renal production of H2O2, increased NRF2 protein expression and decreased glomerular filtration, likely via stimulation of the tubulo-glomerular feedback. Tubular NOX4 overexpression had no obvious impact on kidney morphology, apoptosis, or fibrosis at baseline. Under acute and chronic tubular injury induced by UUO, overexpression of NOX4 in tubular cells did not modify the course of the disease.
    CONCLUSIONS: NOX4 expression was decreased in tubular cells in all types of CKD tested. Tubular NOX4 overexpression did not induce injury in the kidney, and neither modified microvascularization, nor kidney structural lesions in fibrosis.
    Keywords:  Chronic kidney disease; Diabetes; IgA nephropathy; Kidney fibrosis; NOX4; Renal biopsy; Tubular cells
  3. Life Sci Alliance. 2019 Aug;pii: e201800265. [Epub ahead of print]2(4):
    Stalin J, Garrido-Urbani S, Heitz F, Szyndralewiez C, Jemelin S, Coquoz O, Ruegg C, Imhof BA.
      NADPH oxidases catalyze the production of reactive oxygen species and are involved in physio/pathological processes. NOX1 is highly expressed in colon cancer and promotes tumor growth. To investigate the efficacy of NOX1 inhibition as an anticancer strategy, tumors were grown in immunocompetent, immunodeficient, or NOX1-deficient mice and treated with the novel NOX1-selective inhibitor GKT771. GKT771 reduced tumor growth, lymph/angiogenesis, recruited proinflammatory macrophages, and natural killer T lymphocytes to the tumor microenvironment. GKT771 treatment was ineffective in immunodeficient mice bearing tumors regardless of their NOX-expressing status. Genetic ablation of host NOX1 also suppressed tumor growth. Combined treatment with the checkpoint inhibitor anti-PD1 antibody had a greater inhibitory effect on colon carcinoma growth than each compound alone. In conclusion, GKT771 suppressed tumor growth by inhibiting angiogenesis and enhancing the recruitment of immune cells. The antitumor activity of GKT771 requires an intact immune system and enhances anti-PD1 antibody activity. Based on these results, we propose blocking of NOX1 by GKT771 as a potential novel therapeutic strategy to treat colorectal cancer, particularly in combination with checkpoint inhibition.