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 5

Silvestrol alters chemosensitivity in Pten+/–Eμ-Myc and Eμ-Myc/eIF4E tumors in vivo.

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Silvestrol alters chemosensitivity in Pten+/–Eμ-Myc and Eμ-Myc/eIF4E tum...
(A) Silvestrol sensitizes Pten+/–Eμ-Myc tumors to the effects of doxorubicin in vivo. Kaplan-Meier plot showing tumor-free survival of mice bearing Pten+/–Eμ-Myc tumors following treatment with doxorubicin (Dxr, solid black line; n = 10), rapamycin (Rap, dashed green line; n = 9), rapamycin and doxorubicin (Rap + Dxr; solid blue line; n = 8), silvestrol (Sil, solid red line; n = 10), or silvestrol and doxorubicin (Sil + Dxr, dashed red line; n = 8). (B) Silvestrol does not alter drug response in Eμ-Myc/Bcl-2 tumors in vivo. Kaplan-Meier plot showing tumor-free survival of mice bearing Eμ-Myc/Bcl-2 tumors following treatment with Dxr (n = 9), Sil (n = 7), or Sil + Dxr (n = 8). (C) Silvestrol sensitizes Eμ-Myc/eIF4E tumors to the effects of Dxr in vivo. Kaplan-Meier plot showing tumor-free survival of mice bearing Eμ-Myc/eIF4E tumors following treatment with Rap + Dxr (n = 10), Dxr (n = 11), Sil (n = 10), or Sil + Dxr (n = 10). (D) Western blot analysis of Eμ-myc/eIF4E (lane 1) and Pten+/–Eμ-Myc lymphomas (lanes 2–6). Lysates prepared from Eμ-myc/eIF4E or Pten+/–Eμ-Myc lymphomas from untreated (lanes 1, 2, and 4) and rapamycin- (lane 3), doxorubicin- (lane 5), and silvestrol-treated (lane 6) animals were subjected to immunoblotting for analysis of phosphorylated and total ribosomal S6 protein (p-S6 and S6) and Akt (p-Akt and Akt). (E) Silvestrol inhibits translation in Pten+/–Eμ-Myc tumors in vivo. Mice bearing Pten+/–Eμ-Myc tumors were injected with MeOH or silvestrol (0.2 mg/kg). Cytoplasmic extracts were prepared from tumors 4 hours later and resolved on 10%–50% sucrose gradients by centrifugation in an SW40 rotor at 150,000 g for 2 hours. Fractions were collected and monitored using an ISCO UA-6 UV detector. Plotted are results of 1 representative experiment of 3 that showed similar results. The positions in the gradients of 40S and 80S ribosomes are labeled, and the polysome/monosome (P/M) ratios are indicated.