GREEN TEA POLYPHENOLS MEDIATED APOPTOSIS IN INTESTINAL EPITHELIAL CELLS BY A FADD-DEPENDENT PATHWAY

Colorectal cancer is the most common malignant complication in patients with chronic inflammatory bowel disease (IBD). In addition, these patients are at risk for developing painful complications during chemotherapy due to cytotoxic effects of drugs currently in use. Past studies have suggested a protective effect of tea consumption on gastrointestinal (GI) malignancies. Green tea polyphenols (GrTP) inhibited carcinogen-induced GI tumors in rodents and induced apoptosis in various carcinoma cell lines. We hypothesized that GrTP and its polyphenolic compounds regulate apoptosis in the intestinal epithelia. In this study, the effects of GrTP and its polyphenolics on apoptosis was evaluated in intestinal epithelial, IEC-6, cells grown to 85% confluency. GrTP (400-800 mg/ml) induced DNA fragmentation in a dose dependent fashion. Higher concentrations (>800 mg/ml) induced a mixed apoptosis and cytolysis. Epithelial cells exposed to GrTP and a major polyphenol, EGCG, but not EGC or EC, increased caspase activities in a time and dose dependent manner. The caspase inhibitors rescued cells from GrTP and EGCG-induced cell death. Concomitantly, GrTP resulted in activation of fatty acid synthase (Fas)-associated protein with death domain (FADD) and recruitment to Fas/CD95 domain 30 minutes following treatment. While GrTP also blocked NF-κB activation, an NFκ-B inhibitor (MG132) only promoted cytolysis. In conclusion, these data demonstrated GrTP and EGCG induced apoptosis in intestinal epithelia mediated by caspase-8 through a FADD dependent pathway. Future investigation may warrant preventive as well as therapeutic strategies for GrTP in GI malignancy.