1586

Increased expression of cyclooxygenase-2 (COX-2) appears to play an important role in the development of colorectal cancer, and the level of COX-2 expression is regulated by various factors including activation of members of the EGFR family of receptor tyrosine kinases. We previously reported that (-)-epigallocatechin-3-gallate (EGCG), the major biologically active component of green tea, inhibits activation of the EGFR and HER2 receptors, and multiple downstream signaling pathways in the HT29 colon cancer cell line (Shimizu, M. et al., Proc. AACR, 45, #4029, 931, 2004). In this study we examined the effects of EGCG on expression of COX-2 in the SW837 colon cancer cell line that expresses high levels of this protein. We found that these cells also express high levels and constitutive activation of the EGFR, HER2, and HER3 receptors. When treated for 48 hours, the IC50 value for growth inhibition of these cells was about 20 ?g/ml. Treatment of SW837 cells with this concentration of EGCG caused a decrease in the phosphorylated (i.e. activated) forms of the EGFR, HER2, and HER3 proteins within 6 hours after addition of this compound, and at 6 to 12 hours caused a decrease in the phosphorylated forms of the ERK and Akt proteins. Within 6 to 12 hours there was a decrease in cellular levels of both COX-2 protein and mRNA, and within 48 hours the cells displayed apoptosis. Reporter assays indicated that EGCG inhibited the transcriptional activity of the COX-2, AP-1, c-fos, and NF-?B promoters. EGCG also caused a decrease in production of PGE2, a major product of COX-2. With a longer incubation time, 96 hours, a very low dose (1.0 ?g/ml) of EGCG also caused inhibition of cell growth, inhibition of activation of the EGFR, HER2, and HER3 receptors, a decrease in the level of the COX-2 protein and apoptosis in SW837 cells. Taken together, our findings suggest that EGCG can inhibit expression of COX-2 and PGE2 production in colon cancer cells by inhibiting activation of members of the EGFR family and their downstream signaling pathways. These findings extend previous evidence that EGCG, when used alone or in combination with other agents, may be useful in the chemoprevention or treatment of colorectal cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]