Abstract
Insulin-like growth factor-1 (IGF-1) is an important growth and survival factor in multiple myeloma (MM). Here, we demonstrate that IGF-1 induces significant down-regulation of the proapoptotic BH3-only protein Bim in MM cells. Reduced Bim levels by RNA interference (RNAi) protected cells from drug-induced cell death. The IGF-1-mediated down-regulation of Bim was the result of (1) reduced transcription by activation of the Akt pathway and inactivation of the transcription factor FoxO3a, (2) increased proteasome-mediated degradation of the Bim extra-long protein by activation of the mitogen-activated protein kinase pathway, and (3) epigenetic regulation of both the Bim and the FoxO3a promoter. Treatment of cells with the histone deacetylase inhibitor LBH589 resulted in a clear up-regulation in the expression of Bim. Furthermore, the methylation inhibitor 5-aza-2'deoxycytidine (decitabine) significantly increased the effects of LBH589. On IGF-1 treatment, the Bim promoter region was found to be unmethylated, whereas chromatin immunoprecipitation analysis of the IGF-1-treated cells showed both a reduced histone H3 tail Lys9 (H3K9) acetylation and an increased H3K9 dimethylation, which contributed actively to its silencing. These data identify a new mechanism in the IGF-1-dependent survival of MM cells and emphasize the need for IGF-1-targeted drug therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / genetics*
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Bcl-2-Like Protein 11
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / physiology
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Down-Regulation / physiology
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Epigenesis, Genetic / physiology*
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / physiology*
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Gene Silencing
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Histones / metabolism
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Humans
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Hydroxamic Acids / pharmacology
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Immunoglobulin G / pharmacology
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Indoles
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Insulin-Like Growth Factor I / metabolism*
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Insulin-Like Growth Factor I / pharmacology
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Kidney / cytology
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Melphalan / pharmacology
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Membrane Proteins / genetics*
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Multiple Myeloma / genetics*
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Multiple Myeloma / pathology
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Panobinostat
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Processing, Post-Translational
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Proto-Oncogene Proteins / genetics*
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Histones
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Hydroxamic Acids
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Immunoglobulin G
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Indoles
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Membrane Proteins
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Proto-Oncogene Proteins
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antineoplastic agent K 18
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Insulin-Like Growth Factor I
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Panobinostat
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Phosphatidylinositol 3-Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Melphalan