Abstract
We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-kappaB (NF-kappaB)-driven interleukin-6 (IL6) expression. In addition to its physiologic immune function as an acute stress cytokine, sustained elevated expression levels of IL6 promote chronic inflammatory disorders, aging frailty, and tumorigenesis. Our results in estrogen-unresponsive fibroblasts, mitogen- and stress-activated protein kinase (MSK) knockout cells, and estrogen receptor (ER)-deficient breast tumor cells show that phytoestrogenic isoflavones can selectively block nuclear NF-kappaB transactivation of specific target genes (in particular IL6), independently of their estrogenic activity. This occurs via attenuation of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK activity, which further down-regulates MSK-dependent NF-kappaB p65 and histone H3 phosphorylation. As constitutive NF-kappaB and MSK activity are hallmarks of aggressive metastatic ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chromatin / genetics
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Chromatin / metabolism
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Estradiol / pharmacology
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Estrogen Receptor alpha / metabolism*
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fibroblasts / physiology
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / physiology
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Genes, Reporter
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Genistein / pharmacology
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Histone Acetyltransferases / metabolism
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Histone Deacetylases / metabolism
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Humans
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Interleukin-6 / biosynthesis
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Interleukin-6 / genetics
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Isoflavones / pharmacology*
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MAP Kinase Signaling System / drug effects
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Mice
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NF-kappa B / biosynthesis*
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Phosphorylation / drug effects
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Promoter Regions, Genetic
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Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors*
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism
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Transcription Factor RelA / biosynthesis
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Transcription Factor RelA / genetics
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Transcriptional Activation / drug effects
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Chromatin
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Estrogen Receptor alpha
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Interleukin-6
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Isoflavones
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NF-kappa B
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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Estradiol
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daidzein
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Genistein
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Histone Acetyltransferases
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Ribosomal Protein S6 Kinases, 90-kDa
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mitogen and stress-activated protein kinase 1
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Histone Deacetylases
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biochanin A