Epidemiological and experimental evidence suggests that increased consumption of soy can reduce the risk for developing prostate cancer (PCa). Isoflavones have been identified as one group of biologically active components in soy thought to be responsible, in part, for this anticancer activity. The 3 major isoflavones found in soy are the glycoside derivatives of genistein, daidzein, and glycitein. Several lines of evidence suggest that the isoflavones genistein and daidzein may protect against PCa. However, the anticancer activity of glycitein has not been extensively investigated.
The objective of the first study was to examine the effects of soy isoflavones on the activation of the extracellular signal-regulated kinase (ERK1/2) pathway in noncancerous prostate epithelial cells (RWPE-1). The ERK1/2 cascade is involved in PCa progression and its activation may be associated with prevention of this disease. Data presented in the first study show that glycitein is the most potent activator of ERK1/2 signaling as compared with other soy isoflavones. Glycitein-induced ERK1/2 activation was sustained for at least 2 hours and decreased cellular proliferation by 40%. Sustained ERK1/2 activation is thought to induce cellular differentiation in the prostate epithelium.
The sustained ERK1/2 responsed elicited by glycitein in the first study lead to the hypothesis that glycitein may induce differentiation of the RWPE-1 cell line. Loss of cellular differentiation of the two primary differentiated prostate epithelial cells, luminal and basal cells, contributes to the progression of PCa. Soy isoflavones have been shown to induce cellular differentiation in a number of tissues. However, glycitein-induced differentiation in the prostate has not been examined. Cellular differentiation was characterized by cytokeratin expression. Data presented in this study show that glycitein significantly reduced the expression of luminal cell markersyet maintained the expression of basal cell markers. These data suggest that glycitein may induce basal cell differentiation in prostate epithelial cells. The ability of glycitein to induce basal cell differentiation may represent a novel mechanism of preserving this cell population and reducing PCa risk.
Data from the first two studies of this dissertation show that glycitein is a unique isoflavone that induces a robust ERK1/2 response and induces cellular differentiation of prostate epithelial cells. Structurally, glycitein is the only soy isoflavone with a methoxy group. The third hypothesis was that isoflavones with methoxy groups have greater antiproliferative and ERK1/2 responses in prostate cells as compared with nonmethylated isoflavones. To test this hypothesis, noncancerous, precancerous, and cancerous cells were treated with nonmethylated and methylated isoflavones. The results of this study show that although the red clover isoflavones biochanin A and formononetin are methylated, ERK1/2 activation is similar to that of genistein and daidzein. All isoflavones inhibited the proliferation of these cell lines with greater potency in the noncancerous and precancerous cells. However, glycitein-induced ERK1/2 activation was the only isoflavone with associated antiproliferative effects of early stage prostate cells. These results suggest that the position of the methoxy group may be important for the bioactivity of isoflavones. Furthermore, isoflavones may have greater anticancer activity during noncancerous and precancerous stages of PCa.