Akt3 induces oxidative stress and DNA damage by activating the NADPH oxidase via phosphorylation of p47 <sup>phox</sup>
Christos Polytarchou, Maria Hatziapostolou, Tung On Yau, Niki Christodoulou, Philip W. Hinds, Filippos Kottakis, Ioannis Sanidas, Philip N. Tsichlis
Abstract
Significance Although the three Akt isoforms share mechanisms of activation and exhibit overlaps in their downstream signaling pathways, significant differences are now being uncovered. Here, we show that among Akt isoforms, Akt3 preferably phosphorylates p47 phox and activates NADPH oxidase, resulting in robust induction of reactive oxygen species (ROS). Akt3-induced ROS activate the DNA damage response and upregulate p53 expression. Consequently, the proliferation rate of Akt3-expressing cells is reduced, an effect reversed by p53 loss. In cancer, Akt3 expression correlates with the abundance of p53; however, tumors can adapt to high Akt3 activity by inactivating the DNA damage response. These findings reveal differences in the regulation of ROS by Akt isoforms, which may be exploited therapeutically for Akt3-driven cancers.