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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Apoptosis / drug effects*
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics*
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cells, Cultured
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Down-Regulation / drug effects
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Drug Evaluation, Preclinical
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Drug Synergism
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Eukaryotic Initiation Factor-4E / antagonists & inhibitors
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Eukaryotic Initiation Factor-4E / metabolism
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Eukaryotic Initiation Factor-4G / antagonists & inhibitors
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Eukaryotic Initiation Factor-4G / metabolism
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Humans
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Hydrazones
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Nitro Compounds / administration & dosage
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Nitro Compounds / pharmacology*
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Protein Binding / drug effects
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Protein Biosynthesis / drug effects*
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Protein Biosynthesis / genetics
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RNA Cap-Binding Proteins / antagonists & inhibitors
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RNA Cap-Binding Proteins / physiology
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
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TNF-Related Apoptosis-Inducing Ligand / administration & dosage
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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Thiazoles / administration & dosage
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Thiazoles / pharmacology*
Substances
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4EGI-1 compound
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Eukaryotic Initiation Factor-4E
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Eukaryotic Initiation Factor-4G
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Hydrazones
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Nitro Compounds
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RNA Cap-Binding Proteins
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNF-Related Apoptosis-Inducing Ligand
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Thiazoles