Translational regulator eIF2α in tumor

The eukaryotic translation initiation factor 2 alpha (eIF2 alpha) is the regulatory subunit of eIF2 which can be inactivated by phosphorylation. In the adaptive response to various microenvironmental stresses, phosphorylation of eIF2 alpha (p-eIF2 alpha) by specific kinases significantly downregulates global protein synthesis while selectively upregulates the activating transcription factor 4 (ATF4) translation. The ATF4 is a transcription activator that can translocate into nucleus and upregulate genes involved in amino acid synthesis, redox balance, protein maturation, and degradation which lead to the activation of both autophagy and apoptosis. During tumor progression, adaptive response facilitates tumor cell survival and growth under severe stresses. Therefore, eIF2 alpha phosphorylation significantly promotes tumor progression and resistance to therapy. However, there is also evidence showing that p-eIF2 alpha exerts suppressive effects on tumorigenesis. Current understanding of the roles eIF2 alpha plays in tumor is still incomplete and needs further investigation. This review addresses on the past and current efforts to delineate the molecular mechanisms of eIF2 alpha in tumorigenesis, tumor progression, resistance to therapy, and tumor cachexia as well as the translational promise of therapeutic applications targeting eIF2 alpha-related signaling pathway.