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
- Research Support, Non-U.S. Gov't
MeSH terms
- Animals
- Apoptosis / drug effects
- Apoptosis / physiology
- Apoptosis Regulatory Proteins / genetics*
- Bcl-2-Like Protein 11
- Cell Line, Tumor
- Cell Survival / drug effects
- Cell Survival / physiology
- Down-Regulation / physiology
- Epigenesis, Genetic / physiology*
- Forkhead Box Protein O3
- Forkhead Transcription Factors / genetics
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic / physiology*
- Gene Silencing
- Histones / metabolism
- Humans
- Hydroxamic Acids / pharmacology
- Immunoglobulin G / pharmacology
- Indoles
- Insulin-Like Growth Factor I / metabolism*
- Insulin-Like Growth Factor I / pharmacology
- Kidney / cytology
- Melphalan / pharmacology
- Membrane Proteins / genetics*
- Mice
- Mice, Inbred C57BL
- Mitogen-Activated Protein Kinase 1 / metabolism
- Mitogen-Activated Protein Kinase 3 / metabolism
- Multiple Myeloma / genetics*
- Multiple Myeloma / pathology
- Panobinostat
- Phosphatidylinositol 3-Kinases / metabolism
- Protein Processing, Post-Translational
- Proto-Oncogene Proteins / genetics*
Substances
- Apoptosis Regulatory Proteins
- BCL2L11 protein, human
- Bcl-2-Like Protein 11
- Bcl2l11 protein, mouse
- FOXO3 protein, human
- Forkhead Box Protein O3
- Forkhead Transcription Factors
- Histones
- Hydroxamic Acids
- Immunoglobulin G
- Indoles
- Membrane Proteins
- Proto-Oncogene Proteins
- antineoplastic agent K 18
- Insulin-Like Growth Factor I
- Panobinostat
- Phosphatidylinositol 3-Kinases
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- Melphalan