Attenuation of mitogen- and stress-activated protein kinase-1-driven nuclear factor-kappaB gene expression by soy isoflavones does not require estrogenic activity.
Cancer Res
; 66(9): 4852-62, 2006 May 01.
Article
in En
| MEDLINE
| ID: mdl-16651441
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gene Expression Regulation
/
NF-kappa B
/
Ribosomal Protein S6 Kinases, 90-kDa
/
Estrogen Receptor alpha
/
Isoflavones
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Res
Year:
2006
Document type:
Article
Affiliation country:
Bélgica