Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F.
Proc Natl Acad Sci U S A
; 108(3): 1046-51, 2011 Jan 18.
Article
en En
| MEDLINE
| ID: mdl-21191102
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Biosíntesis de Proteínas
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Benzoatos
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Modelos Moleculares
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Factor 4F Eucariótico de Iniciación
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Linfoma
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2011
Tipo del documento:
Article