Ribavirin targets eIF4E dependent Akt survival signaling.

Biochemical and Biophysical Research Communications
Keith TanKatherine L B Borden

Abstract

The eukaryotic translation initiation factor eIF4E is dysregulated in many cancers. eIF4E, through its mRNA export and translation functions, combinatorially modulates the expression of genes involved in Akt dependent survival signaling. For these activities, eIF4E must bind the 7-methyl guanosine (m(7)G) cap moiety on the 5'-end of mRNAs. We demonstrate that a physical mimic of the m(7)G cap, ribavirin, inhibits eIF4E dependent Akt survival signaling. Specifically, ribavirin impairs eIF4E mediated Akt activation via inhibiting the production of an upstream activator of Akt, NBS1. Consequently, ribavirin impairs eIF4E dependent apoptotic rescue. A ribavirin analog with distinct physico-chemical properties, tiazofurin, does not impair eIF4E activity indicating that only analogs that mimic the m(7)G cap will inhibit eIF4E function. Ribavirin represents a first-in-class strategy to inhibit eIF4E dependent cancers, through competition for m(7)G cap binding. Thus, ribavirin coordinately impairs eIF4E dependent pathways and thereby, potently inhibits its biological effects.

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Citations

Mar 12, 2013·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Martin Carroll, Katherine L B Borden
Mar 19, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Filippa PetterssonWilson H Miller
Jan 6, 2010·Journal of Oncology·Biljana Culjkovic, Katherine L Borden
Jul 16, 2010·Leukemia & Lymphoma·Katherine L B Borden, Biljana Culjkovic-Kraljacic
Jan 19, 2016·Expert Reviews in Molecular Medicine·Chunwan LuYafei Cai
Oct 30, 2013·Basic & Clinical Pharmacology & Toxicology·Gergely OswaldFlorian Lang
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