Control of Oncogenesis by eIF2α Phosphorylation: Implications in PTEN and PI3K–Akt Signaling and Tumor Treatment

Abstract

mRNA translation plays an important role in tumor development and represents a valid target of pharmaceutical intervention in cancer. A key step in mRNA translation involves the regulation of initiation by the eukaryotic initiation factor eIF2. Eukaryotic cells respond to various forms of stress by inducing the phosphorylation of the α-subunit of eIF2 at S51, a modification that leads to protein synthesis inhibition. Phosphorylated eIF2α can act either as a promoter of cell survival or an inducer of cell death in response to distinct stimuli. Increased eIF2α phosphorylation has a cytoprotective function in response to genetic or pharmacological inhibition of the PI3K-Akt pathway but also exhibits a proapoptotic function downstream of the PTEN tumor suppressor, independent of PI3K-Akt signaling inhibition. The functional interplay between the PI3K-Akt and eIF2α phosphorylation pathways may have important implications in the design of anti-tumor therapies that depend on the cell fate decisions of phosphorylated eIF2α.