Eukaryotic cells respond to various forms of stress by blocking mRNA translation initiation via the phosphorylation of the alpha (α) subunit of eIF2 at serine 51 (S51) (eIF2αP). Herein, we demonstrate that increased eIF2αP facilitates the adaptation of cells to oxidative stress through the regulation of Akt. Specifically, genetic inactivation of either eIF2αP or the ER-resident kinase PERK in primary mouse or human fibroblasts increases reactive oxygen species (ROS) production leading to increased DNA damage, Akt hyperactivation and induction of senescence. Contrary to the primary cells, immortalized and tumor cells are tolerant to elevated levels of intrinsic ROS caused by eIF2αP inactivation. Nevertheless, eIF2αP-deficient immortalized or tumor cells are more susceptible than eIF2αP-proficient cells to extrinsic oxidative stress caused by hydrogen peroxide or doxorubicin treatment. Extrinsic oxidative stress leads to the induction of either senescence or death in eIF2αP-deficient tumor cells in vitro and in vivo via impaired Akt activation. Our work concludes that Akt acts downstream of eIF2αP to convey either a pro-senescent or a pro-survival role in a cell-context dependent manner in response to oxidative stress. Also, eIF2αP is a potential pharmacological target for tumor treatment in combinational therapies with drugs that induce oxidative stress.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C51.
Citation Format: Antonis E. Koromilas, Rajesh Kamindla, Andreas I. Papadakis, Urszula Kazimierczak, Philippos Peidis, Shuo Wang, Clara Tenkerian, Jothi-Latha Krishnamoorthy, Maria Hatzoglou, Fawaz G. Haj, Gerardo Ferbeyre, Randal J. Kaufman. eIF2alpha phosphorylation determines cell susceptibility to oxidative stress via Akt activation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C51.
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