title: Translation initiation factor eIF4E is a target for tumor cell radiosensitization.
abstract: A core component in the cellular response to radiation occurs at the level of translational control of gene expression. Because a critical element in translation control is the availability of the initiation factor eIF4E, which selectively enhances the cap-dependent translation of mRNAs, we investigated a regulatory role for eIF4E in cellular radiosensitivity. eIF4E silencing enhanced the radiosensitivity of tumor cell lines but not normal cells. Similarly, pharmacologic inhibition of eIF4E with ribavirin also enhanced tumor cell radiosensitivity. eIF4E attenuation did not affect cell-cycle phase distribution or radiation-induced apoptosis, but it delayed the dispersion of radiation-induced γH2AX foci and increased the frequency of radiation-induced mitotic catastrophe. Radiation did not affect 4E-BP1 phosphorylation or cap-complex formation but it increased eIF4E binding to more than 1,000 unique transcripts including many implicated in DNA replication, recombination, and repair. Taken together, our findings suggest that eIF4E represents a logical therapeutic target to increase tumor cell radiosensitivity.
authors.affiliation: University of South Florida Morsani College of Medicine, Tampa, Florida, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hayman
authors.forename: Eli S
authors.initials: ES
authors.lastname: Williams
authors.forename: Muhammad
authors.initials: M
authors.lastname: Jamal
authors.forename: Uma T
authors.initials: UT
authors.lastname: Shankavaram
authors.forename: Kevin
authors.initials: K
authors.lastname: Camphausen
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Tofilon
mesh_terms: D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D029543:Nucleocytoplasmic Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011836:Radiation Tolerance; D014162:Transfection
chemical_list: D004273:DNA, Neoplasm; C411571:EIF4ENIF1 protein, human; D029543:Nucleocytoplasmic Transport Proteins; D034741:RNA, Small Interfering