title: Targeting the eIF4F translation initiation complex: a critical nexus for cancer development.
abstract: Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor 4F (eIF4F), the key regulator of the mRNA-ribosome recruitment phase of translation initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as antineoplastic agents.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Québec, Canada. The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Québec, Canada. Department of Oncology, McGill University, Montreal, Québec, Canada. jerry.pelletier@mcgill.ca.
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Graff
authors.affiliation: School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Davide
authors.initials: D
authors.lastname: Ruggero
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Québec, Canada. The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Québec, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D039562:Eukaryotic Initiation Factor-4F / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D039562:Eukaryotic Initiation Factor-4F