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Title
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Attenuation of mitogen- and stress-activated protein kinase-1-driven nuclear factor-kappa B gene expression by soy isoflavones does not require estrogenic activity
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Author
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Abstract
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| We have analyzed in molecular detail how soy isoflavones (genistein, daidzein, and biochanin A) suppress nuclear factor-kappa B (NF-kappa B)-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-kappa B 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-kappa B p65 and histone H3 phosphorylation. As constitutive NF-kappa B and MSK activity are hallmarks of aggressive meta- static ER-deficient breast cancer, the MSK signaling pathway may become an attractive target for chemotherapy. |
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Language
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English
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Source (journal)
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Cancer research. - Baltimore, Md, 1941, currens
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Publication
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Baltimore, Md
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Waverly
,
2006
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ISSN
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0008-5472
[print]
1538-7445
[online]
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DOI
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10.1158/0008-5472.CAN-05-2957
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Volume/pages
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66
:9
(2006)
, p. 4852-4862
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ISI
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000237496900040
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Full text (Publisher's DOI)
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