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The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells
Patricia Gomez-Bougie1, Régis Bataille, Martine Amiot
1INSERM, U601, Département de Cancérologie LNC Label, Institut de Biologie, Nantes, France.
Abstract:
Multiple myeloma is a fatal B cell malignancy characterized by the accumulation of plasma cells within the bone marrow. IL-6 is a major survival factor for myeloma cells. Bcl-2 protein family regulates pathways to apoptosis that are activated upon growth factor deprivation. Pro-apoptotic proteins that have only a single Bcl-2 homology domain, BH3-only, are potent inducers of apoptosis. In myeloma cells, Mcl-1 has been shown to be a major anti-apoptotic protein that appears to regulate cell survival through the JAK/STAT pathway. In this study, we examined the regulation of the BH3-only protein Bim and its interaction with Mcl-1. The three major Bim isoforms are expressed in myeloma cells and are negatively regulated by IL-6. Blockade of IL-6 signaling induces an up-regulation of Bim concomitant to Mcl-1 down-regulation. Of major interest, Bim is found strongly associated with Mcl-1 in viable myeloma cells while this interaction is disrupted under apoptosis induction. Of note, while Bim is also found strongly associated to Bcl-2, this interaction is not changed under apoptosis induction. Thus, in myeloma cells, Mcl-1 neutralizes Bim through complex formation and therefore prevents apoptosis. Under apoptosis induction, the disappearance of Mcl-1 allows Bim to exercise its pro-apoptotic function and to activate Bax.
Insights
Interleukin-6 (IL-6) negatively regulates the pro-apoptotic protein Bim in multiple myeloma. Mcl-1 binds Bim, preventing apoptosis, but this interaction disrupts upon apoptosis induction, allowing Bim to trigger cell death.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Multiple myeloma is a fatal plasma cell malignancy.
- Interleukin-6 (IL-6) is crucial for myeloma cell survival.
- The Bcl-2 protein family regulates apoptosis, with BH3-only proteins inducing cell death.
Purpose of the Study:
- To investigate the regulation of the BH3-only protein Bim by IL-6 in multiple myeloma.
- To elucidate the interaction between Bim and the anti-apoptotic protein Mcl-1.
- To understand the role of Mcl-1 in neutralizing Bim and preventing apoptosis.
Main Methods:
- Analysis of Bim isoforms and Mcl-1 expression in myeloma cells.
- Investigating the effect of IL-6 blockade on Bim and Mcl-1 levels.
- Studying the interaction between Bim and Mcl-1 using co-immunoprecipitation.
Main Results:
- All three major Bim isoforms are expressed in myeloma cells and negatively regulated by IL-6.
- IL-6 signaling blockade increases Bim expression while decreasing Mcl-1 levels.
- Bim strongly associates with Mcl-1 in viable myeloma cells, preventing apoptosis.
- This Bim-Mcl-1 interaction is disrupted upon apoptosis induction, enabling Bim to activate Bax.
Conclusions:
- Mcl-1 neutralizes the pro-apoptotic protein Bim through complex formation in multiple myeloma cells.
- Disruption of the Mcl-1-Bim interaction is essential for initiating apoptosis in myeloma.
- Targeting the Mcl-1-Bim interaction could be a therapeutic strategy for multiple myeloma.
