bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2020‒09‒06
five papers selected by
Laia Caja Puigsubira
Uppsala University


  1. Redox Biol. 2020 Jul 13. pii: S2213-2317(20)30843-0. [Epub ahead of print]36 101638
    Jiang J, Huang K, Xu S, Garcia JGN, Wang C, Cai H.
      Increased pulmonary vascular permeability due to endothelial cell (EC) barrier dysfunction is a major pathological feature of acute respiratory distress syndrome/acute lung injury (ARDS/ALI), which is a devastating critical illness with high incidence and excessive mortality. Activation of NADPH oxidase (NOX) induces EC dysfunction via production of reactive oxygen species (ROS). However, the role(s) of NOX isoform(s), and their downstream signaling events, in the development of ARDS/ALI have remained unclear. Cecal Ligation Puncture (CLP) was used to induce preclinical septic ALI in wild-type mice and mice deficient in NOX2 or p47phox, or mice transfected of control siRNA, NOX1 or NOX4 siRNA in vivo. The survival rate of the CLP group at 24 h (26.6%, control siRNA treated) was substantially improved by NOX4 knockdown (52.9%). Mice lacking NOX2 or p47phox, however, had worse outcomes after CLP (survival rates at 0% and 8.3% respectively), whereas NOX1-silenced mice had similar survival rate (30%). NOX4 knockdown attenuated lung ROS production in septic mice, whereas NOX1 knockdown, NOX2 knockout, or p47phox knockout in mice had no effects. In addition, NOX4 knockdown attenuated redox-sensitive activation of the CaMKII/ERK1/2/MLCK pathway, and restored expression of EC tight junction proteins ZO-1 and Occludin to maintain EC barrier integrity. Correspondingly, NOX4 knockdown in cultured human lung microvascular ECs also reduced LPS-induced ROS production, CaMKII/ERK1/2/MLCK activation and EC barrier dysfunction. Scavenging superoxide in vitro and in vivo with TEMPO, or inhibiting CaMKII activation with KN93, had similar effects as NOX4 knockdown in preserving EC barrier dysfunction. In summary, we have identified a novel, selective and causal role of NOX4 (versus other NOX isoforms) in inducing lung EC barrier dysfunction and injury/mortality in a preclinical CLP-induced septic model, which involves redox-sensitive activation of CaMKII/ERK1/2/MLCK pathway. Targeting NOX4 may therefore prove to an innovative therapeutic option that is markedly effective in treating ALI/ARDS.
    Keywords:  Acute lung injury (ALI); Acute respiratory distress syndrome (ARDS); Endothelial barrier dysfunction; Endothelial cell (EC); Endothelial permeability; NADPH oxidase (NOX); NOX1; NOX2; NOX4; Occludin; Reactive oxygen species (ROS); Tight junction; ZO-1; p22phox; p47phox
    DOI:  https://doi.org/10.1016/j.redox.2020.101638
  2. Redox Biol. 2020 Aug 25. pii: S2213-2317(20)30903-4. [Epub ahead of print]37 101698
    Kang KA, Piao MJ, Eom S, Yoon SY, Ryu S, Kim SB, Yi JM, Hyun JW.
      We have previously shown that non-thermal dielectric-barrier discharge (DBD) plasma induces the generation of reactive oxygen species (ROS) in cells; however, the underlying mechanism has not been elucidated. This study aimed to identify the mechanisms through which DBD plasma induces the expression of NADPH oxidase (NOX) family members by epigenetic modification in human keratinocytes (HaCaT). Cell exposure to DBD plasma in 10% oxygen and 90% argon resulted in the generation of ROS, triggering oxidative stress that manifested in various forms, including lipid membrane peroxidation, DNA base modification, and protein carbonylation. DBD plasma upregulated the expression of NOX1, NOX5, and DUOX2 at the mRNA and protein levels; and siRNAs targeting NOX1, NOX5, and DUOX2 attenuated the generation of DBD plasma-induced ROS. DBD plasma upregulated the transcriptional activators TET1, MLL1, and HAT1 and downregulated the transcriptional repressors DNMT1, EZH2, and HDAC1. Additionally, DBD plasma increased the binding of transcriptional activators and decreased the binding of transcriptional repressors to the DUOX2 promoter. Methyl-specific polymerase chain reaction and bisulfite sequencing indicated that DBD plasma decreased methylation at the DUOX2 promoter. These results suggest that DBD plasma induces ROS generation by enhancing the expression of the NOX system through epigenetic DNA and histone modifications.
    Keywords:  DNA methylation; Dielectric-barrier discharge plasma; Histone modification; NOX family; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.redox.2020.101698
  3. Anticancer Res. 2020 Sep;40(9): 5071-5079
    Owada S, Endo H, Okada C, Yoshida K, Shida Y, Tatemichi M.
      BACKGROUND/AIM: Liver cancer has extremely poor prognosis. The cancerous tissues contain hypoxic regions, and the available drugs are poorly effective in hypoxic environments. NADPH oxidase 4 (NOX4), producing reactive oxygen species (ROS), may contribute to cancer malignancy under hypoxic conditions. However, its role in liver cancer has not been examined in detail. Our aim was to explore the effects of setanaxib, a recently developed selective NOX4 inhibitor, in liver cancer cells under hypoxic conditions.MATERIALS AND METHODS: Liver cancer cell lines (HepG2, HLE and Alexander) were treated with hypoxia-mimetic agent cobalt chloride. Cytotoxicity assays, immunoblot analysis and ROS detection assay were performed to detect the effect of setanaxib under hypoxic conditions.
    RESULTS: Setanaxib exhibited hypoxia-selective cytotoxicity and triggered apoptosis in cancer cells. Moreover, setanaxib caused mitochondrial ROS accumulation under hypoxic conditions. Treatment with antioxidants markedly attenuated setanaxib-induced cytotoxicity and apoptosis under hypoxic conditions.
    CONCLUSION: Setanaxib caused mitochondrial ROS accumulation in a hypoxia-selective manner and evoked cancer cell cytotoxicity by inducing apoptosis. Thus, setanaxib has a great potential as a novel anticancer compound under hypoxic conditions.
    Keywords:  Cancer treatment; hypoxia; liver cancer; oxidative stress; setanaxib
    DOI:  https://doi.org/10.21873/anticanres.14510
  4. Mol Cancer Res. 2020 Aug 31. pii: molcanres.0334.2020. [Epub ahead of print]
    Hanley CJ, Henriet E, Sirka OK, Thomas GJ, Ewald AJ.
      Collective invasion can be led by breast cancer cells expressing basal epithelial markers, typified by keratin-14 (KRT14). We analyzed gene expression data from The Cancer Genome Atlas and demonstrated a significant correlation between a KRT14+ invasion signature and a stromal mediated extracellular matrix (ECM) organization module. We then developed a novel co-culture model of tumor organoids with autologous stromal cells. Co-culture significantly increased KRT14 expression and invasion of organoids from both luminal and basal murine breast cancer models. However, stromal cell conditioned medium induced invasion but not KRT14 expression. Cancer cells released TGF-β and that signaling pathway was required for stromal cell-induced invasion and KRT14 expression. Mechanistically, TGF-β induced NOX4 expression in stromal cells and NOX4 inhibition reduced invasion and KRT14 expression. In summary, we developed a novel co-culture model and revealed dynamic molecular interactions between stromal cells and cancer cells that regulate both basal gene expression and invasive behavior. Implications: Fibroblasts within mammary tumors can regulate the molecular phenotype and invasive behavior of breast cancer cells.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0334
  5. Nat Cell Biol. 2020 Sep;22(9): 1049-1055
    Katikaneni A, Jelcic M, Gerlach GF, Ma Y, Overholtzer M, Niethammer P.
      Rapid wound detection by distant leukocytes is essential for antimicrobial defence and post-infection survival1. The reactive oxygen species hydrogen peroxide and the polyunsaturated fatty acid arachidonic acid are among the earliest known mediators of this process2-4. It is unknown whether or how these highly conserved cues collaborate to achieve wound detection over distances of several hundreds of micrometres within a few minutes. To investigate this, we locally applied arachidonic acid and skin-permeable peroxide by micropipette perfusion to unwounded zebrafish tail fins. As in wounds, arachidonic acid rapidly attracted leukocytes through dual oxidase (Duox) and 5-lipoxygenase (Alox5a). Peroxide promoted chemotaxis to arachidonic acid without being chemotactic on its own. Intravital biosensor imaging showed that wound peroxide and arachidonic acid converged on half-millimetre-long lipid peroxidation gradients that promoted leukocyte attraction. Our data suggest that lipid peroxidation functions as a spatial redox relay that enables long-range detection of early wound cues by immune cells, outlining a beneficial role for this otherwise toxic process.
    DOI:  https://doi.org/10.1038/s41556-020-0564-2