Abstract
Interleukin-6 (IL-6) inhibits the growth of melanocytes and of early stage melanoma cells, but not that of advanced melanoma cells. The in vitro IL-6 response can be restored in the highly metastatic melanoma B16-F10.9 by addition of recombinant soluble IL-6 receptor alpha-chain (sIL-6R). The F10.9 cells then undergo irreversible growth-arrest and show increased adherence with changes from epithelioid to spindleoid morphology. The sIL-6R is required for IL-6 to induce a sustained activation of the various Stat transcription factors which bind to specific IL-6 inducible enhancers. The sIL-6R and IL-6 combination causes an increase in the level of the anti-oncogenic transcription factor IRF-1 protein and DNA-binding, which remain elevated for 24 h. The promoter activity of the anti-oncogenic p21/Waf-1/Cip-1 gene is induced and accumulation of the p21 protein is observed. These results illustrate the potent agonist activity of sIL-6R on molecular pathways which could mediate the growth-arrest and differentiation of the metastatic melanoma cells. Previously observed antimetastatic effects of IL-6 therapy in mice bearing F10.9 tumors may be at least partly due to direct growth inhibition and differentiation elicited by sIL-6R present in biological fluids.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / chemistry
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Antigens, CD / genetics
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Antigens, CD / metabolism*
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cell Division / drug effects
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Cell Division / genetics
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Cricetinae
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / drug effects
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Cyclins / genetics
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Cyclins / metabolism
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Humans
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Interferon Regulatory Factor-1
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Interleukin-6 / pharmacology*
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Melanoma / drug therapy
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Melanoma / metabolism
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Melanoma / pathology*
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Mice
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Phosphoproteins / drug effects
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Phosphoproteins / metabolism
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Receptors, Interleukin / chemistry
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Receptors, Interleukin / genetics
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Receptors, Interleukin / metabolism*
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Receptors, Interleukin-6
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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STAT1 Transcription Factor
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Solubility
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Trans-Activators / drug effects
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Tumor Cells, Cultured
Substances
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Antigens, CD
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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IRF1 protein, human
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Interferon Regulatory Factor-1
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Interleukin-6
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Irf1 protein, mouse
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Phosphoproteins
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Receptors, Interleukin
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Receptors, Interleukin-6
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Recombinant Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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Stat1 protein, mouse
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Trans-Activators