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p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells.
Authors: Choi YH; Lee WH; Park KY; Zhang L
Source: Jpn J Cancer Res 2000 Feb;91(2):164-73
Genistein, a natural isoflavonoid phytoestrogen, is a strong inhibitor
of protein tyrosine kinase and DNA topoisomerase II activities.
Genistein has been shown to have anticancer proliferation,
differentiation and chemopreventive effects. In the present study, we
have addressed the mechanism of action by which genistein suppressed
the proliferation of p53-null human prostate carcinoma cells.
Genistein significantly inhibited the cell growth, which effect was
reversible, and induced dendrite-like structure. The inhibitory
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
(WAF1/CIP1) in a p53-independent manner. Following genistein
treatment of cells, an increased binding 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
constructs of the p21 promoter indicated that the response to
genistein could be localized to the 300 base pairs proximal to the
transcription start site. These data suggest that genistein may exert
a strong anticarcinogenic effect, and that this effect possibly
involves an induction of p21, which inhibits the threshold kinase
activities of Cdks and associated cyclins, leading to a G2/M arrest
in the cell cycle progression.