Robert, F., Carrier, M., Rawe, S., Chen, S., Lowe, S. W., Pelletier, J. (May 2009) Altering chemosensitivity by modulating translation elongation. PLoS ONE, 4 (5). e5428.
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Abstract
BACKGROUND: The process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Emu-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents. METHODOLOGY/PRINCIPAL FINDINGS: Here, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Emu-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor. CONCLUSION/SIGNIFICANCE: Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics 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 CSHL Cancer Center Shared Resources > Animal Services |
| Depositing User: | Matt Covey |
| Date: | 1 May 2009 |
| Date Deposited: | 21 Feb 2013 21:24 |
| Last Modified: | 29 Dec 2014 20:10 |
| PMCID: | PMC2671598 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27333 |
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