Genistein, a soy metabolite, is a potential chemopreventive agent against various types of cancer. There are several studies documenting molecular alterations leading to cell cycle arrest and induction of apoptosis in a variety of cancer cell lines; however, its mechanism of action and its molecular targets on human melanoma cells remain unclear. In this study, we monitored that genistein inhibited the cell growth in SK-MEL-2 human melanoma cells. It was found that genistein inhibits cell growth in a dose- dependent manner, which was associated with dendrite-like morphological change and apoptotic cell death. Flow cytometry analysis showed that genistein could cause an arrest at the G2/M phase of the cell cycle, which was associated with a down-regulation of cyclin-dependent kinase (Cdk2) and Cdc2 phosphorylation However, genistein did not affect the levels of Cdk inhibitor p21 (WAF1/CIP1) and tumor suppressor p53 in SK-MEL-2 cells. The induction of apoptotic cell death by genistein was associated with a down-regulation of anti-apoptotic Bid and an inhibition of apoptosis proteins (IAPs) family expression, and up-regulation of Fas and FasL protein. Genistein treatment also induced the proteolytic activation of caspase-3 and a concomitant inhibition and/or degradation of poly (ADP-ribose) polymerase (PARP), phospholipas C-γ1 (PLCγ1) and β-catenin. The present results suggest that genistein has divergent biological function, additional studies will be needed to evaluate the molecular mechanisms of the interaction between genistein and other agents. (Cancer Prev Res 11, 46-57, 2006)

Keywords: Genistein, SK-MEL-2, Cell cycle, Apoptosis