Journal
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Volume 768, Issue -, Pages 74-83Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2014.04.003
Keywords
Chemoprevention; Genistein; Cyclooxygenase-2; NF-kappa B; MCF10A cells
Funding
- Global Core Research Center from the National Research Foundation, Republic of Korea [2012-0001184]
- National Research Foundation of Korea [2011-0030001] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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-kappa B. Genistein failed to inhibit TPA-induced nuclear translocation and DNA binding of NF-kappa B as well as degradation of I kappa B. However, genistein abrogated the TPA-induced transcriptional activity of NF-kappa B as determined by the luciferase reporter gene assay. Genistein inhibited phosphorylation of the p65 subunit of NF-kappa B and its interaction with cAMP regulatory element-binding protein-binding protein (CBP)/p300 and TATA-binding protein (TBP). TPA-induced NF-kappa B 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. (C) 2014 Elsevier B.V. All rights reserved.
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