Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors
Open Access
- 8 March 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (11)
- https://doi.org/10.1073/pnas.2020152118
Abstract
Reactive oxygen species (ROS) can cause cellular damage and promote cancer development. Besides such harmful consequences of overproduction of ROS, all cells utilize ROS for signaling purposes and stabilization of cell homeostasis. In particular, the latter is supported by the NADPH oxidase 4 (Nox4) that constitutively produces low amounts of H2O2. By that mechanism, Nox4 forces differentiation of cells and prevents inflammation. We hypothesize a constitutive low level of H2O2 maintains basal activity of cellular surveillance systems and is unlikely to be cancerogenic. Utilizing two different murine models of cancerogen-induced solid tumors, we found that deletion of Nox4 promotes tumor formation and lowers recognition of DNA damage. Nox4 supports phosphorylation of H2AX (γH2AX), a prerequisite of DNA damage recognition, by retaining a sufficiently low abundance of the phosphatase PP2A in the nucleus. The underlying mechanism is continuous oxidation of AKT by Nox4. Interaction of oxidized AKT and PP2A captures the phosphatase in the cytosol. Absence of Nox4 facilitates nuclear PP2A translocation and dephosphorylation of γH2AX. Simultaneously AKT is left phosphorylated. Thus, in the absence of Nox4, DNA damage is not recognized and the increased activity of AKT supports proliferation. The combination of both events results in genomic instability and promotes tumor formation. By identifying Nox4 as a protective source of ROS in cancerogen-induced cancer, we provide a piece of knowledge for understanding the role of moderate production of ROS in preventing the initiation of malignancies.Funding Information
- Deutsche Forschungsgemeinschaft (SCHR1241/1-1)
- Deutsche Forschungsgemeinschaft (SFB815/TP1)
- Deutsche Forschungsgemeinschaft (SFB815/TP8)
- Deutsche Forschungsgemeinschaft (SFB815/Z1)
- Fraunhofer Gesellschaft (TRIP)
This publication has 83 references indexed in Scilit:
- PP2A inactivation is a crucial step in triggering apoptin-induced tumor-selective cell killingCell Death & Disease, 2012
- DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathwayCell Death & Disease, 2012
- ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescenceOncogene, 2011
- Nox4 regulates Nrf2 and glutathione redox in cardiomyocytes in vivoFree Radical Biology & Medicine, 2011
- Quantification of PtdInsP3 molecular species in cells and tissues by mass spectrometryNature Methods, 2011
- NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesisProceedings of the National Academy of Sciences of the United States of America, 2010
- MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantificationNature Biotechnology, 2008
- γH2AX and cancerNature Reviews Cancer, 2008
- Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTipsNature Protocols, 2007
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976