Figure 4

Signaling pathways modulated by glyceollins in the context of cancer cells. Glyceollins (G) have been shown to directly interact with the estrogen receptor (ER), exerting antagonistic effects on ER-dependent pathways. This anti-estrogenic effect of glyceollins prevents E2-dependent proliferation and angiogenesis. In addition, glyceollins induce cell apoptosis by direct ER genomic or nongenomic (membrane-initiated) effects. The expression of forkhead box M1 (FOXM1), a key regulator of the cell cycle, is downregulated by glyceollins. Cell growth and apoptosis can also be affected by glyceollins through ER-independent pathways. Glyceollins inhibit the activity of cytoplasmic kinases, such as the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling axis. Glyceollins repress the expression of growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and promote the expression of microRNAs (miRs) that act as tumor suppressors. Glyceollins also inhibit cell invasion and metastasis. These effects could be partially mediated by the inhibition of zinc finger E-box binding homeobox 1 (ZEB1) and hypoxia inducible factor 1 (HIF-1) expression as well as of microRNAs that enhance tumorigenesis (see text for references). Solid and dashed lines indicate direct and indirect effects, respectively. (+) indicates promoting effect and (-) indicates inhibiting effect.