Figure 4. Blocking Eμ-Myc-driven Tumor Initiation by Pharmacological Suppression of eIF4F Activity.

A. Kaplan-Meier plot showing lymphoma-free survival of 4 wk old Eμ-Myc mice treated with or without 0.2 mg/kg silvestrol (n=7; p< 0.01) for 23 days. B. Percent B220⁺ cells isolated from 6 wk old C57BL/6 or Eμ-Myc mice that had been treated with vehicle or silvestrol for 2 wks. Error bar represent SEM, n=3. *, p<0.01. C. Percent CD4⁺ and CD11b⁺ cells isolated from 6 wk old C57BL/6 or Eμ-Myc mice that had been treated with vehicle or silvestrol for 2 weeks. Error bar represent SEM, n=3. D. Cell cycle distribution of B220⁺ splenic B cells of the indicated genotype and drug treatments. Results are expressed as the average of three independent experiments. E. In situ TUNEL analysis on freshly isolated splenic cells from 5 wk old mice that had been treated with vehicle or silvestrol for 6 days. n= 3 mice; *, p<0.001 F. Western blot analysis of eIF4F targets in splenic B220⁺ cells isolated from untreated or silvestrol-treated Eμ-Myc or C57BL/6 mice. G. Sensitivity of NIH/3T3 cells to silvestrol. NIH/3T3 or Myc/ER NIH 3T3 cells were exposed to vehicle or 250 nM 4-OHT for 18 hrs and then to silvestrol for an additional 24 hrs at the indicated concentrations. Cell viability was determined using the Sulforhodamine B (SRB) colorimetric assay and is set relative to vehicle-treated cells. Values represent the average of 3 biological replicates and error bars denote SEM. H. Relationship between Myc, eIF4F, and eIF4E effectors leading to increased cell cycle progression and survival advantage during the pre-malignant phase of lymphomagenesis. The + sign indicates that increased eIF4F levels also stimulate c-Myc mRNA translation (Lin et al., 2008).