Phosphorylation of the translation initiation factor eIF2 alpha at serine 51 determines the cell fate decisions of Akt in response to oxidative stress

Phosphorylation of the a subunit of the translation initiation factor eIF2 at serine 51 (eIF2 alpha P) is a master regulator of cell adaptation to various forms of stress with implications in antitumor treatments with chemotherapeutic drugs. Herein, we demonstrate that genetic loss of the eIF2 alpha kinases PERK and GCN2 or impaired eIF2 alpha P by genetic means renders immortalized mouse fibroblasts as well as human tumor cells increasingly susceptible to death by oxidative stress. We also show that eIF2 alpha P facilitates Akt activation in cells subjected to oxidative insults. However, whereas Akt activation has a pro-survival role in eIF2 alpha P-proficient cells, the lesser amount of activated Akt in eIF2 alpha P-deficient cells promotes death. At the molecular level, we demonstrate that eIF2 alpha P acts through an ATF4-independent mechanism to control Akt activity via the regulation of mTORC1. Specifically, eIF2 alpha P downregulates mTORC1 activity, which in turn relieves the feedback inhibition of PI3K resulting in the upregulation of the mTORC2-Akt arm. Inhibition of mTORC1 by rapamycin restores Akt activity in eIF2 alpha P-deficient cells but renders them highly susceptible to Akt-mediated death by oxidative stress. Our data demonstrate that eIF2 alpha P acts as a molecular switch that dictates either cell survival or death by activated Akt in response to oxidative stress. Hence, we propose that inactivation of eIF2 alpha P may be a suitable approach to unleash the killing power of Akt in tumor cells treated with pro-oxidant drugs.