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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.
- Source :
-
Oncogene [Oncogene] 2005 Dec 01; Vol. 24 (54), pp. 8076-9. - Publication Year :
- 2005
-
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-x(L) 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.
- Subjects :
- Apoptosis Regulatory Proteins genetics
Bcl-2-Like Protein 11
Down-Regulation
Gene Expression Regulation, Neoplastic drug effects
Humans
Membrane Proteins genetics
Myeloid Cell Leukemia Sequence 1 Protein
Protein Isoforms genetics
Protein Isoforms metabolism
Proto-Oncogene Proteins genetics
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Apoptosis drug effects
Apoptosis Regulatory Proteins metabolism
Melphalan pharmacology
Membrane Proteins metabolism
Multiple Myeloma drug therapy
Neoplasm Proteins metabolism
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 24
- Issue :
- 54
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 16091744
- Full Text :
- https://doi.org/10.1038/sj.onc.1208949