Akt Determines Cell Fate Through Inhibition of the PERK-eIF2α Phosphorylation Pathway

Inhibition of a stress-response pathway renders tumor cells more susceptible to death induced by inhibitors of phosphoinositide 3-kinase signaling. Increasing the Chances of Death Regulation of mRNA translation affects cell growth, proliferation, and differentiation and involves several eukaryotic initiation factors (eIFs). Cells respond to various stresses by blocking the initiation of translation through the phosphorylation of the eIF2α subunit by a number of kinases, including PERK. Increased signaling by the kinases phosphoinositide 3-kinase (PI3K) and Akt is commonly observed in human cancers and leads to the phosphorylation of several proteins involved in the regulation of cell survival and proliferation. Mounir et al. found that the activity of PERK and the amount of phosphorylated eIF2α (eIF2αP) were increased in cells deficient in Akt signaling. The authors showed that Akt-mediated phosphorylation of PERK inhibited its activity and blocked the phosphorylation of eIF2α. In cells undergoing oxidative or endoplasmic reticulum stress, the PERK-eIF2αP pathway antagonized the activity of Akt. Finally, blocking the PERK-eIF2αP pathway rendered tumor cells more susceptible to death after treatment with inhibitors of PI3K-Akt signaling. These data suggest that Akt can control protein synthesis through the PERK-eIF2αP pathway and that inactivation of PERK and eIF2αP may improve the efficacy of therapies that target PI3K-Akt signaling. Metazoans respond to various forms of environmental stress by inducing the phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) at serine-51, a modification that leads to global inhibition of mRNA translation. We demonstrate induction of the phosphorylation of eIF2α in mammalian cells after either pharmacological inhibition of the phosphoinositide 3-kinase (PI3K)–Akt pathway or genetic or small interfering RNA–mediated ablation of Akt. This increase in the extent of eIF2α phosphorylation also occurred in Drosophila cells and depended on the endoplasmic reticulum (ER)–resident protein kinase PERK, which was inhibited by Akt-dependent phosphorylation at threonine-799. The activity of PERK and the abundance of phosphorylated eIF2α (eIF2αP) were reduced in mouse mammary gland tumors that contained activated Akt, as well as in cells exposed to ER stress or oxidative stress. In unstressed cells, the PERK-eIF2αP pathway mediated survival and facilitated adaptation to the deleterious effects of the inactivation of PI3K or Akt. Inactivation of the PERK-eIF2αP pathway increased the susceptibility of tumor cells to death by pharmacological inhibitors of PI3K or Akt. Thus, we suggest that the PERK-eIF2αP pathway provides a link between Akt signaling and translational control, which has implications for tumor formation and treatment.