The eIF4E/eIF4G Interaction Inhibitor 4EGI-1 Augments TRAIL-mediated Apoptosis Through c-FLIP Down-regulation and DR5 Induction Independent of Inhibition of Cap-Dependent Protein Translation

Neoplasia. 2010 Apr;12(4):346-56. doi: 10.1593/neo.10144.

Abstract

The small molecule 4EGI-1 was identified as an inhibitor of cap-dependent translation initiation owing to its disruption of the eIF4E/eIF4G association through binding to eIF4E. 4EGI-1 exhibits growth-inhibitory and apoptosis-inducing activity in cancer cells; thus, we were interested in its therapeutic efficacy in human lung cancer cells. 4EGI-1, as a single agent, inhibited the growth and induced apoptosis of human lung cancer cells.When combined with the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), enhanced apoptosis-induced activity was observed. As expected, 4EGI-1 inhibited eIF4E/eIF4G interaction and reduced the levels of cyclin D1 and hypoxia-inducing factor-1alpha (HIF-1alpha), both of which are regulated by a cap-dependent translation mechanism. Moreover, 4EGI-1 induced CCAAT/enhancer-binding protein homologous protein-dependent DR5 expression and ubiquitin/proteasome- mediated degradation of cellular FLICE-inhibitory protein (c-FLIP). Small interfering RNA-mediated blockade of DR5 induction or enforced expression of c-FLIP abrogated 4EGI-1's ability to enhance TRAIL-induced apoptosis, indicating that both DR5 induction and c-FLIP down-regulation contribute to enhancement of TRAIL-induced apoptosis by 4EGI-1. However, inhibition of eIF4E/eIF4G interaction by knockdown of eIF4E effectively reduced the levels of cyclin D1 and HIF-1alpha but failed to induce DR5 expression, downregulate c-FLIP levels, or augment TRAIL-induced apoptosis. These results collectively suggest that 4EGI-1 augments TRAIL-induced apoptosis through induction of DR5 and down-regulation of c-FLIP, independent of inhibition of cap-dependent protein translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis / drug effects*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cells, Cultured
  • Down-Regulation / drug effects
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Eukaryotic Initiation Factor-4E / antagonists & inhibitors
  • Eukaryotic Initiation Factor-4E / metabolism
  • Eukaryotic Initiation Factor-4G / antagonists & inhibitors
  • Eukaryotic Initiation Factor-4G / metabolism
  • Humans
  • Hydrazones
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Nitro Compounds / administration & dosage
  • Nitro Compounds / pharmacology*
  • Protein Binding / drug effects
  • Protein Biosynthesis / drug effects*
  • Protein Biosynthesis / genetics
  • RNA Cap-Binding Proteins / antagonists & inhibitors
  • RNA Cap-Binding Proteins / physiology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
  • TNF-Related Apoptosis-Inducing Ligand / administration & dosage
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacology*

Substances

  • 4EGI-1 compound
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factor-4G
  • Hydrazones
  • Nitro Compounds
  • RNA Cap-Binding Proteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • Thiazoles