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


Authors: Bordeleau, M. E.; Robert, F.; Gerard, B.; Lindqvist, L.; Chen, S. M. H.; Wendel, H. G.; Brem, B.; Greger, H.; Lowe, S. W.; Porco, J. A. Jr; Pelletier, J.
Article Title: Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model
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.
Keywords: controlled study; human cell; doxorubicin; drug potentiation; nonhuman; antineoplastic agent; protein function; translation initiation; mouse; animals; mice; apoptosis; phosphatase; cell line; animal experiment; animal model; drug resistance, neoplasm; chemosensitivity; cell line, tumor; hela cells; mice, inbred c57bl; carcinogenesis; drug synergism; dead box protein; messenger rna; screening; proto-oncogene proteins c-akt; pten phosphohydrolase; lymphoma; initiation factor 4e; polyribosomes; tumor growth; disease models, animal; oncogene c myc; tensin; drug sensitivity; rapamycin; sirolimus; eukaryotic initiation factor-4e; poly(adp-ribose) polymerases; ribosome; thapsigargin; 1 o formylaglafoline; benzofuran derivative; silvestrol; benzofurans; eukaryotic initiation factor-4a; peptide chain initiation, translational; triterpenes
Journal Title: Journal of Clinical Investigation
Volume: 118
Issue: 7
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2008-07-01
Start Page: 2651
End Page: 2660
Language: English
DOI: 10.1172/jc134753
PUBMED: 18551192
PROVIDER: scopus
PMCID: PMC2423864
DOI/URL:
Notes: --- - "Cited By (since 1996): 36" - "Export Date: 17 November 2011" - "CODEN: JCINA" - "Source: Scopus"
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  1. Hans Guido Wendel
    72 Wendel