Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species

Oncol Rep. 2015 Oct;34(4):1726-32. doi: 10.3892/or.2015.4155. Epub 2015 Jul 27.


Malignant pleural mesothelioma (MPM) is an aggressive tumor that is characterized by dysregulated growth and resistance to apoptosis. Reactive oxygen species (ROS)-generating NADPH oxidase (Nox) family enzymes have been suggested to be involved in neoplastic proliferation. Both the antioxidant N-acetylcysteine (NAC) and the inhibitor of flavoprotein-dependent oxidase, diphenylene iodonium (DPI), inhibited the cell viability of MPM cells in a dose-dependent manner. To examine whether Nox-mediated ROS generation confers antiapoptotic activity and thus a growth advantage to MPM cells, we analyzed the mRNA expression of Nox family members using quantitative RT-PCR in 7 MPM cell lines and a normal mesothelial cell line. Nox4 mRNA was expressed in all of the examined MPM cell lines, whereas little or no Nox2, Nox3 and Nox5 mRNA expression was detected. In 2 MPM cell lines, Nox4 mRNA expression was significantly higher than that in a normal mesothelial cell line. siRNAs targeting Nox4 suppressed ROS generation and cell viability in the MPM cell lines. In addition, DPI treatment and knockdown of Nox4 attenuated phosphorylation of AKT and ERK. Taken together, our results indicate that Nox4-mediated ROS, at least in part, transmit cell survival signals and their depletion leads to apoptosis, thus highlighting the Nox4-ROS-AKT signaling pathway as a potential therapeutic target for MPM treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / administration & dosage
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mesothelioma / genetics*
  • Mesothelioma / pathology
  • Mesothelioma, Malignant
  • NADPH Oxidase 4
  • NADPH Oxidases / biosynthesis*
  • NADPH Oxidases / genetics
  • Onium Compounds / administration & dosage
  • Oxidative Stress / genetics*
  • RNA, Messenger / biosynthesis
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction / drug effects


  • Onium Compounds
  • RNA, Messenger
  • Reactive Oxygen Species
  • diphenyleneiodonium
  • NADPH Oxidase 4
  • NADPH Oxidases
  • NOX4 protein, human
  • Acetylcysteine