Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappa B in cancer cells versus normal cells

Green tea has shown remarkable anti-inflammatory and cancer chemopreventive effects in many animal tumor bioassays, cell culture systems, and epidemio logical studies. Many of these biological effects of green tea are mediated by epigallocatechin 3-gallate (EGCG), the major polyphenol present therein . We have earlier shown that EGCG treatment results in apoptosis of several cancer cells, but not of normal cells (J. Natl Cancer Inst. 89, 1881-1886 (1997)). The mechanism of this differential response of EGCG is not known. In this study, we investigated the involvement of NF-KB during these differ ential responses of EGCG, EGCG treatment resulted in a dose-dependent (i) i nhibition of cell growth, (ii) G0/G1-phase arrest of the cell cycle, and (i ii) induction of apoptosis in human epidermold carcinoma (A431) cells, but not in normal human epidermal keratinocytes (NHEK), Electromobility shift a ssay revealed that EGCG (10-80 mu M) treatment results in lowering of NF-KB levels in both the cytoplasm and nucleus in a dose-dependent manner in bot h A431 cells and NHEK, albeit at different concentrations. EGCG treatment w as found to result in a dose-based differential inhibition of TNF-alpha- an d LPS-mediated activation of NF-KB in these cells. The inhibition of NF-KB constitutive expression and activation in NHEK was observed only at high co ncentrations, The immunoblot analysis also demonstrated a similar pattern o f inhibition of the constitutive expression as well as activation of NF-kap pa B/p65 nuclear protein. This inhibition of TNF-alpha-caused NF-KB activat ion was mediated via the phosphorylative degradation of its inhibitory prot ein I kappa B alpha. Taken together, EGCG was found to impart differential dose-based NF-kappa B inhibitory response in cancer cells vs normal cells; i,e,, EGCG-mediated inhibition of NF-KB constitutive expression and activat ion was found to occur at much higher dose of EGCG in NHEK as compared to A 431 cells. This study suggests that EC;CG-caused cell cycle deregulation an d apoptosis of cancer cells may be mediated through NF-kappa B inhibition, (C) 2000 Academic Press.