Genistein induces cell apoptosis in MDA-MB-231 breast cancer cells via the mitogen-activated protein kinase pathway

Genistein, an isoflavonoid present in soybeans, exhibits anti-carcinogenic effects. Several studies have shown that genistein inhibits cell proliferation and triggers apoptosis in human breast cancer cells. In this study, we assessed the role of the MEK-ERK cascade in the regulation of genistein-mediated cell apoptosis in MDA-MB-231 cells. The results indicate that genistein, in a concentration-dependent manner, suppresses the protein levels of MEK5, total ERK5, and phospho-ERK5, effects that are consistent with inhibition of cell growth and induction of apoptosis. Exposure of these cells to genistein results in a concentration-dependent decrease in NF-kappa B/p65 protein levels and DNA-binding activity of NF-kappa B. Genistein down-regulates Bcl-2 and up-regulates Bax. NF-kappa B binding sites are present in the promoter of Bcl2, suggesting that genistein might inhibit the expression of Bcl-2 through down-regulation of NF-kappa B. Exposure of MDA-MB-231 cells to genistein results in cleavage of caspase-3 and induction of caspase-3 activity in a concentration-dependent manner. Genistein inhibits NF-kappa B activity via the MEK5/ERK5 pathway: it also inhibits cell growth and induces apoptosis. In conclusion, inhibition of the MEK5/ERK5/NF-KB pathway may be an important mechanism by which genistein suppresses cell growth and induces apoptosis. (C) 2008 Elsevier Ltd. All rights reserved.