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Published on: May 15, 2019
The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction
G Descamps1, P Gomez-Bougie, J Tamburini
1Inserm, U892, Univ Nantes, CNRS, UMR 6299, Nantes, F-44000, France.
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.
Insights
Targeting protein translation with 4EGI-1 effectively induced apoptosis in multiple myeloma cells by disrupting the eIF4F complex. This suggests a promising new therapeutic strategy for this incurable cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cancer cells rely on deregulated oncogenic protein translation.
- The small molecule 4EGI-1 inhibits cap-dependent mRNA translation.
- Multiple myeloma necessitates novel therapeutic strategies.
Purpose of the Study:
- To investigate targeting the translation initiation pathway for myeloma therapy.
- To evaluate the efficacy of 4EGI-1 in multiple myeloma models.
Main Methods:
- Utilized six myeloma cell lines and primary samples.
- Assessed 4EGI-1 effects via AnnexinV staining and caspase activation.
- Analyzed protein expression changes and performed knock-down experiments.
Main Results:
- 4EGI-1 impaired eIF4F complex assembly and reduced eIF4E-regulated proteins.
- 4EGI-1 induced apoptosis in 5/6 myeloma cell lines, linked to mitochondrial pathway activation.
- Noxa induction, triggered by ER stress, was crucial for 4EGI-1-induced apoptosis, with Noxa silencing preventing cell death.
Conclusions:
- Inhibitors targeting the eIF4F translation initiation complex show potential as a novel therapy for multiple myeloma.
- The findings highlight the role of Noxa in mediating 4EGI-1-induced apoptosis in myeloma cells.
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