Phytochemical glyceollins, isolated from soy, mediate antihormonal effects through estrogen receptor alpha and beta.

The flavonoid family of phytochemicals, particularly those derived from soy, has received attention regarding their estrogenic activity as well as their effects on human health and disease. In addition to these flavonoids other phytochemicals, including phytostilbene, enterolactone, and lignans, possess endocrine activity. The types and amounts of these compounds in soy and other plants are controlled by both constitutive expression and stress-induced biosynthesis. The health benefits of soy-based foods may, therefore, be dependent upon the amounts of the various hormonally active phytochemicals within these foods. The aim was to identify unique soy phytochemicals that had not been previously assessed for estrogenic or antiestrogenic activity. Here we describe increased biosynthesis of the isoflavonoid phytoalexin compounds, glyceollins, in soy plants grown under stressed conditions. In contrast to the observed estrogenic effects of coumestrol, daidzein, and genistein, we observed a marked antiestrogenic effect of glyceollins on ER signaling, which correlated with a comparable suppression of 17 beta-estradiol-induced proliferation in MCF-7 cells. Further evaluation revealed greater antagonism toward ER alpha than ER beta in transiently transfected HEK 293 cells. Competition binding assays revealed a greater affinity of glyceollins for ER alpha vs. ER beta, which correlated to greater suppression of ER alpha signaling with higher concentrations of glyceollins. In conclusion, we describe the phytoalexin compounds known as glyceollins, which exhibit unique antagonistic effects on ER in both HEK 293 and MCF-7 cells. The glyceollins as well as other phytoalexin compounds may represent an important component of the health effects of soy-based foods.

PI3-K/AKT regulation of NF-kappaB signaling events in suppression of TNF-induced apoptosis.

We found that in MCF-7 breast carcinoma cells, PI3K and Akt suppressed a dose-dependent induction of apoptosis by tumor necrosis factor alpha (TNF). PI3K and Akt stimulated NF-kappaB activation in a dose-dependent manner, suggesting a common link between these two pathways. TNF has been shown to activate both an apoptotic cascade, as well as a cell survival signal through NF-kappaB. PI3K and AKT cell survival signaling were correlated with increased TNF-stimulated NF-kappaB activity in MCF-7 cells. We demonstrate that while both TNFR1 and NIK are partially involved in Akt-induced NF-kappaB stimulation, a dominant negative IkappaBalpha completely blocked Akt-NF-kappaB cross-talk. PI3K-Akt signaling activated NF-kappaB through both TNFR signaling-dependent and -independent mechanisms, potentially representing a mechanism by which Akt functions to suppress apoptosis in cancer.