Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model
Marie-Eve Bordeleau, … , John A. Porco Jr., Jerry Pelletier
Marie-Eve Bordeleau, … , John A. Porco Jr., Jerry Pelletier
Published June 12, 2008
Citation Information: J Clin Invest. 2008;118(7):2651-2660. https://doi.org/10.1172/JCI34753.
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Research Article Oncology

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.

Authors

Marie-Eve Bordeleau, Francis Robert, Baudouin Gerard, Lisa Lindqvist, Samuel M.H. Chen, Hans-Guido Wendel, Brigitte Brem, Harald Greger, Scott W. Lowe, John A. Porco Jr., Jerry Pelletier

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Figure 6

Silvestrol synergizes with doxorubicin to induce apoptosis in Pten+/–Eμ-Myc lymphoma cells in vivo.

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Silvestrol synergizes with doxorubicin to induce apoptosis in Pten+/–Eμ-...
(A) Representative micrographs (original magnification, ×200) of Pten+/–Eμ-Myc lymphoma sections stained with H&E and TUNEL. C57BL/6 mice bearing well-palpable tumors were injected with vehicle, silvestrol, or rapamycin. Twenty-four hours later, the mice were injected again with silvestrol or rapamycin alone or in combination with doxorubicin. Three and 6 hours after treatment, tumors were extracted and stained. (B) Amount of tumor cells positive for TUNEL staining per 1,000 cells following the treatments described in A. The cell count was obtained from 4 different fields taken from 2 different sections. Results are expressed as mean ± SD. In vehicle-treated cells, there were 36 ± 1 TUNEL-positive cells/1,000 cells. (C) Western blot analysis of Pten+/–Eμ-Myc lymphomas treated as described in A. Tumor cells were extracted and lysed and the amount of cleaved poly(ADP-ribose) polymerase (c-PARP) and tubulin determined by Western blotting.