Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47 phox

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Polytarchou, C. ORCID: 0000-0002-1948-7934, Hatziapostolou, M. ORCID: 0000-0003-2493-7028, Yau, T.O., Christodoulou, N. ORCID: 0000-0002-7802-0904, Hinds, P.W., Kottakis, F., Sanidas, I. and Tsichlis, P.N., 2020. Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47 phox. Proceedings of the National Academy of Sciences, 117 (46), pp. 28806-28815. ISSN 0027-8424

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Official URL: https://doi.org/10.1073/pnas.2017830117

Abstract

Akt activation up-regulates the intracellular levels of reactive oxygen species (ROS) by inhibiting ROS scavenging. Of the Akt isoforms, Akt3 has also been shown to up-regulate ROS by promoting mitochondrial biogenesis. Here, we employ a set of isogenic cell lines that express different Akt isoforms, to show that the most robust inducer of ROS is Akt3. As a result, Akt3-expressing cells activate the DNA damage response pathway, express high levels of p53 and its direct transcrip-tional target miR-34, and exhibit a proliferation defect, which is rescued by the antioxidant N-acetylcysteine. The importance of the DNA damage response in the inhibition of cell proliferation by Akt3 was confirmed by Akt3 overexpression in p53 −/− and INK4a −/− /Arf −/− mouse embryonic fibroblasts (MEFs), which failed to inhibit cell proliferation , despite the induction of high levels of ROS. The induction of ROS by Akt3 is due to the phosphorylation of the NADPH oxidase subunit p47 phox , which results in NADPH oxidase activation. Expression of Akt3 in p47 phox−/− MEFs failed to induce ROS and to inhibit cell proliferation. Notably, the proliferation defect was rescued by wild-type p47 phox , but not by the phosphorylation site mutant of p47 phox. In agreement with these observations, Akt3 up-regulates p53 in human cancer cell lines, and the expression of Akt3 positively correlates with the levels of p53 in a variety of human tumors. More important, Akt3 alterations correlate with a higher frequency of mutation of p53, suggesting that tumor cells may adapt to high levels of Akt3, by inactivating the DNA damage response. Akt isoforms | NADPH oxidase | oxidative stress | DNA damage | cancer

Item Type:

Journal article

Publication Title:

Proceedings of the National Academy of Sciences

Creators:

Polytarchou, C., Hatziapostolou, M., Yau, T.O., Christodoulou, N., Hinds, P.W., Kottakis, F., Sanidas, I. and Tsichlis, P.N.

Publisher:

National Academy of Sciences

Date:

17 November 2020

Volume:

117