p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells

Genistein. a natural isoflavonoid phytoestrogen, is a strong inhibitor of p rotein tyrosine kinase and DNA topoisomerase II activities. Genistein has b een shown to have anticancer proliferation, differentiation and chemopreven tive effects. In the present study, we have addressed the mechanism of acti on by which genistein suppressed the proliferation of p53-null human prosta te carcinoma cells. Genistein significantly inhibited the cell growth, whic h effect was reversible, and induced dendrite-like structure, The inhibitor y effects of genistein on cell growth proliferation were associated with a G2/M arrest in cell cycle progression concomitant with a marked inhibition of cyclin B1 and an induction of Cdk inhibitor p21 (WAFI/CIP1) in a p53-ind ependent manner. Following genistein treatment of cells, an increased bindi ng of p21 with Cdk2 and Cdc2 paralleled a significant decrease in Cdc2 and Cdk2 kinase activity with no change in Cdk2 and Cdc2 expression. Genistein also induced the activation of a p21 promoter reporter construct, utilizing a sequence distinct from the p53-binding site, Analysis of deletion constr ucts of the p21 promoter indicated that the response to genistein could be localized to the 300 base pairs proximal to the transcription start site. T hese data suggest that genistein may exert a strong anticarcinogenic effect , and that this effect possibly involves an induction of p21, which inhibit s the threshold kinase activities of Cdks and associated cyclins, leading t o a G2/M arrest in the cell cycle progression.