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

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 attracti...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-01, Vol.108 (3), p.1046-1051
Main Authors: Cencic, Regina, Hall, David R., Robert, Francis, Du, Yuhong, Min, Jaeki, Li, Lian, Qui, Min, Lewis, Iestyn, Kurtkaya, Serdar, Dingledine, Ray, Fu, Haian, Kozakov, Dima, Vajda, Sandor, Pelletier, Jerry, Housman, David E.
Format: Article
Language:English
Subjects:
Animals
Benzoates - pharmacology
Biological Sciences
Blotting, Western
Cancer
Cells
DNA damage
Drug interactions
Eukaryotic Initiation Factor-4F - antagonists & inhibitors
Eukaryotic Initiation Factor-4F - biosynthesis
Eukaryotic Initiation Factor-4G - antagonists & inhibitors
Eukaryotic initiation factors
High-Throughput Screening Assays
Lymphoma
Lymphoma - drug therapy
Lymphoma - metabolism
Messenger RNA
Mice
Models, Molecular
Molecules
Peptide initiation factors
Protein Binding
Protein Biosynthesis - physiology
Protein synthesis
Ribonucleic acid
Ribosomes
RNA
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1011477108