Abstract
Interleukin 6 (IL-6) is the major survival factor for myeloma tumor cells and induces signaling through the STAT proteins. We report that one STAT family member, Stat3, is constitutively activated in bone marrow mononuclear cells from patients with multiple myeloma and in the IL-6-dependent human myeloma cell line U266. Moreover, U266 cells are inherently resistant to Fas-mediated apoptosis and express high levels of the antiapoptotic protein Bcl-xL. Blocking IL-6 receptor signaling from Janus kinases to the Stat3 protein inhibits Bcl-xL expression and induces apoptosis, demonstrating that Stat3 signaling is essential for the survival of myeloma tumor cells. These findings provide evidence that constitutively activated Stat3 signaling contributes to the pathogenesis of multiple myeloma by preventing apoptosis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Apoptosis / immunology*
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DNA-Binding Proteins / metabolism*
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DNA-Binding Proteins / physiology
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Gene Expression Regulation / drug effects
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Humans
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Immunity, Innate / drug effects
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Mice
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Multiple Myeloma / genetics
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Multiple Myeloma / immunology
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Multiple Myeloma / metabolism*
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Multiple Myeloma / pathology
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Promoter Regions, Genetic / drug effects
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Protein-Tyrosine Kinases / physiology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Receptors, Interleukin-6 / physiology
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STAT3 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Trans-Activators / metabolism*
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Trans-Activators / physiology
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Transcription, Genetic / drug effects
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Transfection
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Tumor Cells, Cultured
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Tyrphostins / pharmacology
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bcl-X Protein
Substances
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Antineoplastic Agents
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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DNA-Binding Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Interleukin-6
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse
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Trans-Activators
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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bcl-X Protein
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Protein-Tyrosine Kinases