Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model

Bordeleau, M. E., Robert, F., Gerard, B., Lindqvist, L., Chen, S. M., Wendel, H. G., Brem, B., Greger, H., Lowe, S. W., Porco, J. A., Pelletier, J. (July 2008) Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest, 118 (7). 2651- 2660.

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URL: http://www.ncbi.nlm.nih.gov/pubmed/18551192
DOI: 10.1172/JCI34753

Abstract

Disablement of cell death programs in cancer cells contributes to drug resistance and in some cases has been associated with altered translational control. As eukaryotic translation initiation factor 4E (eIF4E) cooperates with c-Myc during lymphomagenesis, induces drug resistance, and is a genetic modifier of the rapamycin response, we have investigated the effect of dysregulation of the ribosome recruitment phase of translation initiation on tumor progression and chemosensitivity. eIF4E is a subunit of eIF4F, a complex that stimulates ribosome recruitment during translation initiation by delivering the DEAD-box RNA helicase eIF4A to the 5′ end of mRNAs. eIF4A is thought to prepare a ribosome landing pad on mRNA templates for incoming 40S ribosomes (and associated factors). Using small molecule screening, we found that cyclopenta[b]benzofuran flavaglines, a class of natural products, modulate eIF4A activity and inhibit translation initiation. One member of this class of compounds, silvestrol, was able to enhance chemosensitivity in a mouse lymphoma model in which carcinogenesis is driven by phosphatase and tensin homolog (PTEN) inactivation or elevated eIF4E levels. These results establish that targeting translation initiation can restore drug sensitivity in vivo and provide an approach to modulating chemosensitivity.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
therapies
therapies > cancer drugs - see diseases-cancer-drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > translation
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: 1 July 2008
Date Deposited: 25 Feb 2013 15:01
Last Modified: 25 Feb 2013 15:01
PMCID: PMC2423864
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27632

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