Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap.

摘要: Abstract The eukaryotic translation initiation factor eIF4E is deregulated in many human cancers, and its overexpression cells leads to malignant transformation. Oncogenic properties of are directly linked ability bind 7-methyl guanosine the 5′ mRNA. Here, we observe that antiviral analogue ribavirin binds with micromolar affinity at functional site used by mRNA cap, competes eIF4E:mRNA binding, and, low concentrations, selectively disrupts subcellular organization transport mRNAs posttranscriptionally regulated eIF4E, thereby reducing levels oncogenes such as cyclin D1. Ribavirin potently suppresses eIF4E-mediated oncogenic transformation murine vitro, tumor growth a mouse model eIF4E-dependent squamous cell carcinoma vivo, colony formation acute myelogenous leukemia derived from patients. These findings describe specific, potent, unforeseen mechanism action ribavirin. Quantum mechanical NMR structural studies offer directions for development derivatives improved cytostatic properties. In all, ribavirin's association may provide pharmacologic means interruption posttranscriptional networks maintain enhance neoplasia malignancy cancer.