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Phosphorylation of the  α  subunit of the translation initiation factor eIF2 at serine 51 (eIF2 α 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 α  kinases PERK and GCN2 or impaired eIF2 α 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 α P facilitates Akt activation in cells subjected to oxidative insults. However, whereas Akt activation has a pro-survival role in eIF2 α P-proficient cells, the lesser amount of activated Akt in eIF2 α P-deficient cells promotes death. At the molecular level, we demonstrate that eIF2 α P acts through an ATF4-independent mechanism to control Akt activity via the regulation of mTORC1. Specifically, eIF2 α 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 α P-deficient cells but renders them highly susceptible to Akt-mediated death by oxidative stress. Our data demonstrate that eIF2 α 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 α P may be a suitable approach to unleash the killing power of Akt in tumor cells treated with pro-oxidant drugs.

Phosphorylation of the translation initiation factor eIF2α at serine 51 determines the cell fate decisions of Akt in response to oxidative stress