The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction.

Abstract

BACKGROUND:

Cancer cells are frequently addicted to deregulated oncogenic protein translation. The small molecule 4EG-I selectively inhibits the cap-dependent translation of mRNAs. As multiple myeloma is an incurable disease that requires new therapeutic approaches, we investigated whether targeting the translation initiation pathway could be a target for myeloma therapy.

METHODS:

Six myeloma cell lines and primary samples were included in this study. The 4EGI-1 effect was determined by AnnexinV staining and caspase activation. Modification of Bcl-2 protein expression was analysed, and the significance of modified proteins was analysed by knock-down experiments.

RESULTS:

We demonstrated that 4EGI-1 impaired the assembly of the eIF4F complex and decreased the expression of the eIF4E-regulated proteins in myeloma cells. Furthermore, we showed that 4EGI-1 induced strong apoptosis in five out of six myeloma cell lines. Apoptosis is associated with the activation of the intrinsic mitochondrial pathway. The 4EGI-1 triggered Noxa induction only in cells undergoing apoptosis through endoplasmic reticulum (ER) stress. Furthermore, Noxa silencing prevented myeloma cells from 4EGI-1-induced apoptosis. Finally, Noxa induction led to a disruption of Mcl-1/Bim complexes in parallel to the generation of 'Mcl-1-free Noxa'.

CONCLUSION:

Our results suggested that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for multiple myeloma therapy.

• Authors: G Descamps, P Gomez-Bougie, J Tamburini, A Green, D Bouscary, S Maïga, P Moreau, S Le Gouill, C Pellat-Deceunynck, M Amiot
• Journal: British journal of cancer (Br J Cancer) Vol. 106 Issue 10 Pg. 1660-7 (May 08 2012) ISSN: 1532-1827 [Electronic] England
• PMID: 22510748 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4EGI-1 compound
• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Eukaryotic Initiation Factor-4F
• Hydrazones
• Membrane Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitro Compounds
• PMAIP1 protein, human
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Thiazoles

Topics

• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Bcl-2-Like Protein 11
• Cell Line, Tumor
• Eukaryotic Initiation Factor-4F (antagonists & inhibitors, physiology)
• Humans
• Hydrazones
• Membrane Proteins (metabolism)
• Multiple Myeloma (drug therapy, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitro Compounds (pharmacology)
• Peptide Chain Initiation, Translational (drug effects)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (analysis, metabolism, physiology)
• Thiazoles (pharmacology)