An Update on the Effects of Glyceollins on Human Health: Possible Anticancer Effects and Underlying Mechanisms

Abstract

Biologically active plant-based compounds, commonly referred to as phytochemicals, can influence the expression and function of various receptors and transcription factors or signaling pathways that play vital roles in cellular functions and are then involved in human health and diseases. Thus, phytochemicals may have a great potential to prevent and treat chronic diseases. Glyceollins, a group of phytoalexins that are isolated from soybeans, have attracted attention because they exert numerous effects on human functions and diseases, notably anticancer effects. In this review, we have presented an update on the effects of glyceollins in relation to their potential beneficial roles in human health. Despite a growing number of studies suggesting that this new family of phytochemicals can be involved in critical cellular pathways, such as estrogen receptor, protein kinase, and lipid kinase signaling pathways, future investigations will be needed to better understand their molecular mechanisms and their specific significance in biomedical applications.

Keywords: breast cancer; dietary compounds; estrogen receptor; glyceollins; human health; phytochemicals; signaling pathways.

Figure 1

Schematic summary of the targets of glyceollins.

Figure 2

Glyceollin biosynthesis pathway. The isoflavone daidzein serves as the metabolic precursor for the rapid production of glyceollins. Daidzein is produced through the isoflavonoid branch of the phenylpropanoid pathway starting from L-phenylalanine. Under stress, daidzein is transformed into (6aR, 11aR)-3,9 dihydroxypterocarpan. This molecule is metabolized by CYP93A1 into (-) glycinol. Then, a dimethylallyl group is attached to the glycinol at position 2, which leads to the production of glyceollin II and III, or at position 4, which leads to the production of glyceollin I. These two steps are catalyzed by trihydroxypterocarpan dimethylallyl transferase and glyceollin synthase, respectively.

Figure 3

Estrogen receptor (ER) structure and action. The schematic structures of the two human ERα and ERβ and the percentage of homology between the different domains (annotated by the letters A to F) are indicated (A). Domains involved in DNA binding (DBD), ligand binding (LBD), ligand-independent transactivation function 1 (AF-1), and ligand-dependent transactivation function 2 (AF-2) are shown. The number of amino acids for each receptor is also indicated on the right side. Estradiol (E2) mediates numerous phenotypic effects in cells by binding to and activating ERs (B). E2 enters the cell through the lipid membranes and binds ER, which can be present in the cytoplasm and the nucleus. The activated ER forms a dimer to tightly fix chromatin directly at the estrogen-responsive element (ERE) sites or indirectly at activator protein 1 (AP1) or specificity protein 1 (Sp1) sites. ER is then able to remodel chromatin by recruiting cofactors and activating RNA polymerase II (Pol II), at target genes (genomic action). Besides, ERs can use rapid non-genomic action through the interaction with intracellular kinases (mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K),…) and the growth factor (GF) receptor (GFR) pathways.

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.

Figure 5

Glyceollins enhance the NGF effect on PC12-ER differentiation. PC12-ER transfected with ERα and PC12-Cont transfected with empty plasmid (cartridge) cells were treated for 72 h with 5 ng of nerve growth factor (NGF) associated with solvent (black), E2 10^-9 M (blue), various concentrations of glyceollin I (GI, gray) or glyceollin II (GII, red), or a mixture (1:1) of both GI and GII (green). PC12 cells were then photographed to determine the percentage of cells bearing neurites. The results are expressed as the percentage of cells bearing neurites in the presence of NGF + E2. The results are the mean of at least three independent experiments ± SEM. ** p-value < 0.01 and *** p-value < 0.001, with one-way ANOVA and Bonferroni’s post hoc test used to compare the control cells (NGF + solvent) with the other treatments. ### p-value < 0.001, with one-way ANOVA and Bonferroni’s post hoc test used to compare the NGF + E2-treated cells with the other treatments.