Resveratrol (RSVL), a phytoalexin found in abundance in grapes and other grape-related products, has been shown to be antiproliferative and protective against various types of cancers, including breast cancer. However, the precise underlying mechanisms are not well understood. In this study, we show that treatment with RSVL induces growth inhibition and apoptosis in a highly invasive and metastatic breast cancer cell line MDA-MB-231. Cleavage of caspase-3 and PARP and fragmentation of DNA were observed following exposure to RSVL. Co-treatment with pan-caspase inhibitor completely prevents cell death induced by RSVL. We found that RSVL-induced apoptosis correlates with sustained activation of ERK1/2 and suppression of Bcl-2 expression. Inhibition of ERK1/2 activation by its specific inhibitor or small interfering RNA reverses the effect of RSVL on Bcl-2 suppression and inhibits apoptosis, while overexpression of MEK1, which is directly upstream of both ERK1 and ERK2, enhances apoptosis induced by RSVL. Moreover, ERK1/2 was found to act upstream of caspase-3 to induce apoptosis, while it was not directly involved in caspase-3 cleavage. The other closely related MAPK members, p38 and JNK are not involved in apoptosis induced by RSVL in MDA-MB-231 cells. These results suggest that activation of ERK1/2 is required for RSVL-induced apoptosis in MDA-MB-231 cells.

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