Table 2.
The Molecular Mechanisms of the Chemopreventive Effects of Soy Isoflavones in Prostate Cancer.
| Molecular Event | Target Genes/Proteins | Soy Isoflavones | Invitro/invivo System |
|---|---|---|---|
| Cell-cycle regulators | p21, p27, p53, cyclin B1, cyclin B2*, cyclin D1, Cyclin E, CDK2, CDK4, CDK7*, FOXO1, MAPK, CDKI-1A*, CDKI-2A*, CHEK2* | Genistein, daidzein and equol | LNCaP, PC-3, DU-145, LAPC-4 |
| IGF-1 (Insulin-Like Growth Factor-1) signaling | p-IGF-1R, p-Src, p-Akt, p-GSk-3β, IRS-1 | Genistein, daidzein and equol | PC-3, AT6.3, LNCaP and DU-145 |
| TGFβ (transforming growth factor β) signaling pathway | TGFβ, MAPK-Activated Protein Kinase 2*, p38 MAPK, HSP27*, MMP2 | Genistein | PC3 and PC3-M |
| Wnt/β-catenin signaling | β-catenin, E-cadherin | Genistein | PC-3 |
| Tyrosine kinase inhibition | p-EGFR*, p-Akt*, p-GSK-3β*, mTOR-p70S6k*, p-FOXO3a*, p-Src* | Genistein, daidzein and glycetin | LNCaP, LNCaP-p53(GOF), 22Rv1, and C4-2B |
| Apoptosis | PTEN, Bcl-2*, Bax*, caspase-3*, survivin, elafin, PAR-2, NFκB, proteasome* | Genistein, daidzein and glycetin | LNCaP, PC-3, DU145 and BPH-1 |
| cell differentiation | cytokeratin 18*, cytokeratin 5* and P63* | Genistein, daidzein, glycetin and equol | RWPE-1 cells line and TRAMP mouse model |
| Autophagy | mTOR-p70S6k* | Genistein | LNCaP and 22Rv1 |
| Antioxidant defense and DNA repair | (GPx)-1*, glutathione reductase, microsomal glutathione S-transferase 1, metallothionein, MnSOD, catalase, GADD45*, p53 | Genistein | LNCaP, PC-3, LAPC-4 and DU-145 |
| Prostaglandin metabolism and action | PGE(2), COX2, prostaglandin receptors EP4 and FP, PGDH (hydroxyprostaglandin dehydrogenase) | Genistein | LNCaP and PC-3 |
| Cancer stem cells | hTERT (human telomerase reverse transcriptase) | Genistein | PC3/(CIC), LNCaP and DU-145 |
| DNA methylation | BRCA1*, GSTP1*, EPHB2*, RASSF1A*, (BTG3/ANA/APRO4), PTEN*, CYLD*, p53*, FOXO3a*, p21* (WAF1/CIP1/KIP1)*, p16* INK4a*, DNMT and methyl-binding domain proteins | Genistein and daidzein | LNCaP, DU-145, DuPro and PC-3 |
| Histone modifications | H3-K9*, Akt*, PTEN*, Cyclin D*, p53* and FOXO3a* | Genistein | LNCaP and PC-3 |
| Regulation of mi-RNA | miR-29a and miR-1256 | Genistein and daidzein | LNCaP, VCaP, PC-3, C4–2B, ARCaP cell lines and in human tumor tissues |
| Inhibition of angiogenesis | VEGF, HIF-1, NF-kappaB, angiopoietin 2 (ANGPT2), PD-ECGF*, IL6*, IL-8*, endoglin*, CD31*, FGF1*, IGF1*, FGFR3*, PECAM1*, CXCL10* | Genistein and daidzein | LNCap, PC-3, DU-145 and C4-2B cell lines and LNCaP xenograft mouse model |
| Inhibition of metastasis | MMP-2, Focal adhesion kinase (FAK), p38 MAPK, and HSP27, Osteopontin (OPN)* | Genistein | PC3 and LNCaP cell lines, TRAMP mouse model and LNCaP xenograft SCID mouse model |
| Inhibition of EMT | E-Cadherin, N-Cadherin, Vimentin, Fibronectin, Twist, Snail | Genistein | IA8-ARCaP |
| Regulation of immune cell function | TNF-α*, granulocyte monocyte-colony stimulating factor (GM-CSF)*, IL-10 | Genistein | PC-3/PI cell line and R3327 MAT-Lu xenograft rat model |
| Increase sensitivity to radio and chemotherapy | Akt*, p53*, p21*, PARP*, Bcl-xL*, Bax*, survivin*, HIF1-α* | Genistein | LNCaP, PC-3, LNCaP-R273H, C4-2 and Cds1 cell lines and PC-3 orthotopic metastatic mouse model, |
| Androgen receptor mediated pathway | AR, PSA, HDAC6-Hsp90 | Genistein | LNCaP cell line, TRAMP mouse model and rat model |
| Estrogen receptor mediated pathway | ER-α, ER-β | Genistein | LNCaP and PC-3 cell lines, Sprague-Dawley rats and TRAMP mice |
*
The asterisk indicates that high pharmacological doses were applied to obtain the effect on target genes/proteins.