Abstract
We recently showed that monoclonal antibodies (mAbs) against beta2-microglobulin (beta2M) have a remarkably strong apoptotic effect on myeloma cells. The mAbs induced apoptosis by recruiting major histocompatibility complex (MHC) class I to lipid rafts, activated c-Jun N-terminal kinase (JNK), and inhibited phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways. Growth and survival cytokines such as interleukin-6 (IL-6) and insulin-like growth factor-I (IGF-I), which could protect myeloma cells from dexamethasone-induced apoptosis, did not affect mAb-mediated cell death. This study was undertaken to elucidate the mechanisms underlying anti-beta2M mAb-induced PI3K/Akt and ERK inhibition and the inability of IL-6 and IGF-I to protect myeloma cells from mAb-induced apoptosis. We focused on lipid rafts and confirmed that these membrane microdomains are required for IL-6 and IGF-I signaling. By recruiting MHC class I into lipid rafts, anti-beta2M mAbs excluded IL-6 and IGF-I receptors and their substrates from the rafts. The mAbs not only redistributed the receptors in cell membrane, but also abrogated IL-6- or IGF-I-mediated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), PI3K/Akt, and Ras/Raf/ERK pathway signaling, which are otherwise constitutively activated in myeloma cells. Thus, this study further defines the tumoricidal mechanism of the mAbs and provides strong evidence to support the potential of these mAbs as therapeutic agents for myeloma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology*
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / drug effects
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Apoptosis Regulatory Proteins / metabolism
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Blotting, Western
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Cell Line, Tumor
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Extracellular Signal-Regulated MAP Kinases / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Histocompatibility Antigens Class I / drug effects*
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Histocompatibility Antigens Class I / metabolism
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Humans
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Immunoprecipitation
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Insulin-Like Growth Factor I / drug effects
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Insulin-Like Growth Factor I / metabolism
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Interleukin-6 / metabolism
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MAP Kinase Kinase 4 / drug effects
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MAP Kinase Kinase 4 / metabolism
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Membrane Microdomains / chemistry
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Membrane Microdomains / drug effects*
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Membrane Microdomains / metabolism
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Multiple Myeloma / metabolism*
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Receptors, Growth Factor / drug effects
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Receptors, Growth Factor / metabolism
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Signal Transduction / drug effects
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beta 2-Microglobulin / antagonists & inhibitors*
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beta 2-Microglobulin / immunology
Substances
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Antibodies, Monoclonal
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Apoptosis Regulatory Proteins
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Histocompatibility Antigens Class I
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Interleukin-6
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Receptors, Growth Factor
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beta 2-Microglobulin
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Insulin-Like Growth Factor I
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 4