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Melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex

Oncogene volume 24, pages 8076–8079 (2005)Cite this article

Abstract

Multiple myeloma (MM) is a rapidly fatal plasma-cell malignancy that evolves mainly in the bone marrow. Melphalan is widely used to treat patients with MM but as yet its mechanisms of action are poorly documented. In the current study, we demonstrate that melphalan induces a drastic downregulation of Mcl-1L, Bcl-xL and BimEL in human melphalan-sensitive myeloma cells while the most potent proapoptotic isoforms, BimL and S, are affected to a lesser extent. Moreover, Mcl-1L and BimEL disappearance is associated with the generation of proapoptotic cleaved forms generated by a caspase cleavage. In myeloma cells, we have previously shown that Mcl-1 neutralizes the proapoptotic function of Bim and therefore, prevents the activation of death effectors. In this study, we demonstrate that melphalan disrupts the Mcl-1/Bim complex whereas the Bcl-2/Bim complex is not modified. The disappearance of full length Mcl-1 allows the release of Bim isoforms, particularly L and S, which can exert their proapoptotic function and leads to Bax activation and cytochrome c release. Thus, we can hypothesize that the cleaved 26 kDa proapoptotic Mcl-1 and the 19 and 12 kDa of Bim, generated during melphalan treatment could contribute to the amplification loop of apoptosis.

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Abbreviations

BH:

Bcl-2 homology (domain)

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Acknowledgements

This work was supported by The Ligue Nationale contre le Cancer (équipe labelisée 2005).

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  1. Département de recherche en cancérologie, INSERM, UMR601, Equipe 5 labélisée L N C 2005, Institut de biologie, 9 quai Moncousu, 44093, Nantes, cedex 01, France

    Patricia Gomez-Bougie, Lisa Oliver, Steven Le Gouill, Régis Bataille & Martine Amiot

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Gomez-Bougie, P., Oliver, L., Le Gouill, S. et al. Melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex. Oncogene 24, 8076–8079 (2005). https://doi.org/10.1038/sj.onc.1208949

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