DAIDZEIN INHIBITS INSULIN OR INSULIN-LIKE GROWTH FACTOR-1-MEDIATED SIGNALING IN CELL-CYCLE PROGRESSION OF SWISS 3T3 CELLS

An isoflavone compound, daidzein, inhibits the cell proliferation of Swiss 3T3 cells. Analysis of entry in S phase of Swiss 3T3 cells reveals that daidzein blocked cell cycle G(1) phase progression 4.6 h after stimulation by bombesin plus insulin. After removal of daidzein, insulin or insulin-like growth factors (IGFs) reinitiate cell cycle progression of daidzein-blocked cells without further addition of bombesin. The order in the mitogenic action of insulin or IGFs is as follows: IGF-1 (5 ng/ml)much greater than IGF-2 (0.5 mu g/ml)similar or equal to insulin (1 mu g/ml). Studies in vivo of protein kinase activation by mitogenic stimulation reveal that the treatment with daidzein decreased the activation of a MAP2 phosphorylating protein kinase (MAP2 kinase). In vitro kinase assays showed that daidzein inhibits casein kinase II activity, but does not inhibit MAP2 kinase activity. Activation of casein kinase II by polylysine augments the activity of MAP2 kinase in digitonin-permeabilized 3T3 cells. These results suggest that daidzein blocked G(1) phase cell cycle progression of Swiss 3T3 by inhibiting the activity of casein kinase II which is required for the commitment of mitogenic signal by insulin or IGF-1 in G(1) phase.