Hydrogen peroxide formation by Nox4 limits malignant transformation

Abstract

PrecisBy oxidizing AKT and keeping PP2A in the cytosol, the NADPH oxidase Nox4 allows proper DNA damage repair and averts cancer development.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/177055 doi: bioRxiv preprint first posted online Aug. 16, 2017; AbstractReactive 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 H 2 O 2 . We infer that this constitutive H 2 O 2 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. (200 words) 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the NADPH oxidase Nox4, as constitutive source of ROS, prevents malignant transformation and that its pharmacological not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/177055 doi: bioRxiv preprint first posted online Aug. 16, 2017; inhibition as currently aspired by several companies will potentially increase the risk of malignant cell transformation and eventually tumor formation.

NADPH oxidase‐derived reactive oxygen species: Dosis facit venenum

“…Accordingly, knockout of Nox4 promotes the development of solid tumors in pro-inflammatory mouse-models for cancer (Helfinger et al 2017 (Giannoni et al, 2008).…”

The NADPH Oxidase Isoform 1 Contributes to Angiotensin II-Mediated DNA Damage in the Kidney

“…Higher basal levels of DNA damage were recently also observed in vitro, in Nox4-knockout cells [40]. In that study, a role of Nox4 in DNA damage repair was discussed; oxidation of the kinase AKT in the nucleus by Nox4 was necessary to keep the activity of the γ-H2AX-dephosphorylating phosphatase PP2A low [40]. Therefore, loss of Nox4 impaired DNA repair and elevated DNA damage [40].…”

“…In that study, a role of Nox4 in DNA damage repair was discussed; oxidation of the kinase AKT in the nucleus by Nox4 was necessary to keep the activity of the γ-H2AX-dephosphorylating phosphatase PP2A low [40]. Therefore, loss of Nox4 impaired DNA repair and elevated DNA damage [40]. The importance of Nox4 and Nox1 for phosphorylation of γ-H2AX was also shown by Kodama et al [41], although DNA damage was not quantified in their study.…”

“…Strikingly, lack of Nox2 and Nox4 led to a higher basal DNA damage in the kidney of the knockout animals. Higher basal levels of DNA damage were recently also observed in vitro, in Nox4-knockout cells [40]. In that study, a role of Nox4 in DNA damage repair was discussed; oxidation of the kinase AKT in the nucleus by Nox4 was necessary to keep the activity of the γ-H2AX-dephosphorylating phosphatase PP2A low [40].…”

NoxO1 Knockout Promotes Longevity in Mice

“…Slides were washed three times with PBS and were stained with SYBR green. Pictures were taken with a confocal microscope LSM 510 Meta and quantification was done manually by three independent investigators determining the ratio of cell number/cells with comets, as described before [14].…”