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Mutat Res. 2014 Oct;768:74-83. doi: 10.1016/j.mrfmmm.2014.04.003. Epub 2014 Apr 15.

Genistein inhibits phorbol ester-induced NF-κB transcriptional activity and COX-2 expression by blocking the phosphorylation of p65/RelA in human mammary epithelial cells.

Author information

1
Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
2
Department of Food and Nutrition, Sungshin Women's University, Seoul, South Korea.
3
LEGEST, University of Gent, Belgium.
4
Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea. Electronic address: surh@snu.ac.kr.

Abstract

Genistein, an isoflavone present in soy products, has chemopreventive effects on mammary carcinogenesis. In the present study, we have investigated the effects of genistein on phorbol ester-induced expression of cyclooxygenase-2 (COX-2) that plays an important role in the pathophysiology of inflammation-associated carcinogenesis. Pretreatment of cultured human breast epithelial (MCF10A) cells with genistein reduced COX-2 expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). There are multiple lines of evidence supporting that the induction of COX-2 is regulated by the eukaryotic transcription factor NF-κB. Genistein failed to inhibit TPA-induced nuclear translocation and DNA binding of NF-κB as well as degradation of IκB. However, genistein abrogated the TPA-induced transcriptional activity of NF-κB as determined by the luciferase reporter gene assay. Genistein inhibited phosphorylation of the p65 subunit of NF-κB and its interaction with cAMP regulatory element-binding protein-binding protein (CBP)/p300 and TATA-binding protein (TBP). TPA-induced NF-κB phosphorylation was abolished by pharmacological inhibition of extracellular signal-regulated kinase (ERK). Likewise, pharmacologic inhibition or dominant negative mutation of ERK suppressed phosphorylation of p65. The above findings, taken together, suggest that genistein inhibits TPA-induced COX-2 expression in MCF10A cells by blocking ERK-mediated phosphorylation of p65 and its subsequent interaction with CBP and TBP.

KEYWORDS:

Chemoprevention; Cyclooxygenase-2; Genistein; MCF10A cells; NF-κB

PMID:
24742714
DOI:
10.1016/j.mrfmmm.2014.04.003
[Indexed for MEDLINE]

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