Activations of Stat1 and Erk are involved in the resveratrol-induced human esophageal cancer cell apoptosis. Free

B123

Resveratrol(trans-3,5,4'-trihydroxystilbene), a naturally occurring polyphenolic compound, was first isolated in 1940 as a constituent of the roots of white hellebore, and it was also found abundantly in red wines, berries and peanuts. Besides cardioprotective effects, more and more researches show that resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation and induce apoptosis in a wide variety of tumor cells. However, its mechanism of action is not fully understood. Our recent studies showed that resveratrol induced cytotoxicity, growth inhibition, and apoptosis in human esophageal cancer EC109 cells. The growth-inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1 and Bax; down-regulation of cyclin D1 and Bcl-2. The p21 expression level was found to be up regulated at 30mins after 50 μM resveratrol treatment and the level of p21 increased with the time of treatment. Cyclin D1 expression level begins to decrease at 2 hour of treatment and showed time-dependent manner. ERK which is an important survival signal in MAPK pathways, was activated 10 mins after resveratrol treatment with increasing concentration of resveratrol from 10 μM to 100 μM. The effect of resveratol on the pERK level was also shown a time and dose dependent fashion with the highest level at 24 hrs and then dramatically decreased at 48 hrs. But it did not affect MAPK level based on western blotting analyses. Using western blot analysis, stat1 was also found to be activated at 5 hours of treatment, remarkably increased at 24hours, and reached to the highest level at 48 hours in a dose-dependent manner. This effect was also confirmed by immunofluorescence and EMSA experiments. This is the first report to demonstrate stat1 activation in the reseveratrol-induced human esophageal cancer apoptosis. Activated stat1 can bind to the promoter of p21 to induce expression of this protein. p21 blocked the cell cycle in G1-S by inhibiting the cyclin D. The role of Erk activation in resveratrol-induced apoptosis is under investigation. This work was partially supported by grants HKU7218/02M and HKU7395/03M from UGC of Hong Kong.