Hydrogen peroxide formation by Nox4 limits malignant transformation

Reactive oxygen species (ROS) can cause cellular damage and are thought to promote cancer-development. Nevertheless, under physiological conditions, all cells constantly produce ROS, either as chemical by-products or for signaling purpose. During differentiation cells induce the NADPH oxidase Nox4, which constitutively produces low amounts of H2O2. We infer that this constitutive H2O2 is unlikely to be carcinogenic and may rather maintain basal activity of cellular surveillance systems.Utilizing two different murine tumor models we demonstrate that Nox4 prevents malignant transformation and facilitated the recognition of DNA-damage. Upon DNA-damage repair is initiated as consequence of phosphorylation of H2AX (γH2AX). Repair only occurs if nuclear activity of the γH2AX-dephosphorylating phosphatase PP2A is kept sufficiently low, a task fulfilled by Nox4: Nox4 continuously oxidizes AKT, and once oxidized AKT captures PP2A in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of γH2AX. Simultaneously the proportion of active, phosphorylated AKT is increased. Thus, DNA-damage is not recognized and the increase in AKT activity promotes proliferation. The combination of both events resulted in genomic instability and tumor initiation.With the identification of the first cancer-protective source of reactive oxygen species, Nox4, the paradigm of reactive-oxygen species-induced initiation of malignancies should be revised.SignificanceThe stereotype of ROS produced by NADPH oxidases as cause of malignant diseases persists generalized since decades. We demonstrate that the NADPH oxidase Nox4, as constitutive source of ROS, prevents malignant transformation and that its pharmacological inhibition as currently aspired by several companies will potentially increase the risk of malignant cell transformation and eventually tumor formation.PrecisBy oxidizing AKT and keeping PP2A in the cytosol, the NADPH oxidase Nox4 allows proper DNA damage repair and averts cancer development.