Altering chemosensitivity by modulating translation elongation.

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.

• Authors: Francis Robert, Marilyn Carrier, Svea Rawe, Samuel Chen, Scott Lowe, Jerry Pelletier
• Journal: PloS one (PLoS One) Vol. 4 Issue 5 Pg. e5428 ( 2009) ISSN: 1932-6203 [Electronic] United States
• PMID: 19412536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccnd1 protein, mouse
• DNA Primers
• Depsipeptides
• Eukaryotic Initiation Factor-4E
• Harringtonines
• Mcl1 protein, mouse
• Myc protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• Quassins
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• Cyclin D1
• didemnins
• Homoharringtonine
• Cycloheximide
• PTEN Phosphohydrolase
• Pten protein, mouse
• bruceantin

Topics

• Animals
• Base Sequence
• Cell Line, Tumor
• Cyclin D1 (metabolism)
• Cycloheximide (pharmacology)
• DNA Primers (genetics)
• Depsipeptides (pharmacology)
• Drug Resistance, Neoplasm
• Eukaryotic Initiation Factor-4E (genetics)
• Female
• Genes, bcl-2
• Genes, myc
• Harringtonines (pharmacology)
• Homoharringtonine
• Lymphoma (drug therapy, genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mutation
• Myeloid Cell Leukemia Sequence 1 Protein
• PTEN Phosphohydrolase (genetics)
• Peptide Chain Elongation, Translational (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Quassins (pharmacology)
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (genetics)