Mechanistic Role of eIF4E in the Hallmarks of Cancer: A Translational Control Perspective.

Abstract

Cancer progression is driven by coordinated dysregulation of signaling and gene-expression programs that sustain multiple hallmarks of malignancy. Eukaryotic initiation factor 4E (eIF4E) has emerged as an important determinant of this translational reprogramming by preferentially enhancing the synthesis of proteins that support oncogenic phenotypes. This review critically examines the mechanistic evidence linking eIF4E-dependent translation to major cancer hallmarks, including sustained proliferative signaling, evasion of apoptosis, tumor-promoting inflammation, angiogenesis, invasion, and metastasis. We discuss how dysregulated eIF4E activity, driven in part by the PI3K/AKT/mTOR and MAPK/MNK pathways, promotes selective translation of oncogenic, survival, stress-response, hypoxia-, and epithelial-mesenchymal transition-associated factors. We further examine evidence implicating eIF4E in the regulation of p53- and telomerase reverse transcriptase (TERT)-dependent pathways, highlighting potential links to genomic instability and replicative immortality. Finally, we evaluate pharmacological strategies targeting eIF4E and discuss the opportunities and challenges of exploiting eIF4E-dependent translational and metabolic vulnerabilities for cancer therapy. Collectively, the evidence supports eIF4E as a therapeutically relevant translational regulator whose functional activity, rather than expression alone, may help define tumor dependencies and inform mechanism-based therapeutic strategies.