There are multiple lines of compelling evidence from epidemiologic and laboratory studies supporting that frequent consumption of green tea is inversely associated with the risk of several types of human cancer and other chronic diseases. The chemopreventive and chemoprotective effects of green tea have been attributed to its polyphenols, and (-)epigallocatechin-3-gallate (EGCG) has been recognized as a major active constituent of green tea. Abnormal upregulation of cyclooxygenase-2 (COX-2) is implicated in the pathogenesis of several types of malignancies. In the present study, we have examined the effects of EGCG on 12-O-tetradecanoylphorbol-13-acetate (TPA)- induced COX-2 expression in human breast epithelial (MCF-10A) cells. EGCG inhibited TPA-induced COX-2 expression in a concentration dependent manner. EGCG inhibited activation of COX-2 promoter by TPA as determined by using pCOX-2-Luc containing the entire COX-2 promoter region. To elucidate the underlying mechanism of COX-2 down-regulation by EGCG, we examined its effects on the activation of transcriptional factors known to regulate expression of Cox-2. EGCG attenuated the DNA binding and transcriptional activities of nuclear factor-κB (NF-κB), which is one of the major transcription factors known to regulate COX-2 gene expression. EGCG blocked the TPA-induced phosphorylation of IκB-α which is an inhibitory subunit of the NF-κB complex sequestered in the cytoplasm. EGCG also inhibited the DNA binding activity and transcriptional activity of activator protein-1 (AP-1), another transcription factor known to regulate COX-2 expression. Likewise, DNA binding activity of C/EBP was suppressed by EGCG. Therefore, inhibition of TPA-induced COX-2 expression by EGCG is likely to be mediated by blockade of DNA binding activity of NF-κB, AP-1 and C/EBP in the MCF-10A cells.

Keywords: (-)Epigallocatechin-3-gallate (EGCG), Cyclooxygenase-2, TPA, Transcription factor, Human breast epithelial cells