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Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F.

Proceedings of the National Academy of Sciences of the United States of America (2010-12-31)
Regina Cencic, David R Hall, Francis Robert, Yuhong Du, Jaeki Min, Lian Li, Min Qui, Iestyn Lewis, Serdar Kurtkaya, Ray Dingledine, Haian Fu, Dima Kozakov, Sandor Vajda, Jerry Pelletier
ABSTRACT

Deregulation of cap-dependent translation is associated with cancer initiation and progression. The rate-limiting step of protein synthesis is the loading of ribosomes onto mRNA templates stimulated by the heterotrimeric complex, eukaryotic initiation factor (eIF)4F. This step represents an attractive target for anticancer drug discovery because it resides at the nexus of the TOR signaling pathway. We have undertaken an ultra-high-throughput screen to identify inhibitors that prevent assembly of the eIF4F complex. One of the identified compounds blocks interaction between two subunits of eIF4F. As a consequence, cap-dependent translation is inhibited. This compound can reverse tumor chemoresistance in a genetically engineered lymphoma mouse model by sensitizing cells to the proapoptotic action of DNA damage. Molecular modeling experiments provide insight into the mechanism of action of this small molecule inhibitor. Our experiments validate targeting the eIF4F complex as a strategy for cancer therapy to modulate chemosensitivity.

MATERIALS
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Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-15, ascites fluid

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