| Our previous study demonstrated that ginsenoside Rg1 was a unique class of phytoestrogens which activated estrogen-like activities without direct interaction with the estrogen receptor (ER). The present study aims to investigate if Rg1 could exert tissue-selective estrogenic effects in ER-positive target tissues and the molecular mechanism involved in its tissue-selective estrogenic effects.;Our results demonstrated that the estrogenic actions of Rg1 were distinct from those of 17beta-estradiol and its effects were tissue selective. The potent estrogenic effect of Rg1 was only observed in mammary gland in immature female CD-1 mice. Chronic administration of Rg1 did not result in bone protective effects and unwanted simulation of reproductive tissues in OVX mice model in a way that was distinct from 17beta-estradiol which exerted bone protective effects and also the stimulatory effects in uterus. However, Rg1 exerted potential anti-apoptotic effects on cardiovascular tissues and estrogenic effects on brain tissues. In addition, we demonstrated that Rg1, but not estren, failed to exert stimulatory effects in UMR106 cells with expressed lower level of ER, suggesting that the estrogenic effects of Rg1 in bone may require higher abundance of ER. For the molecular mechanisms study, differential signaling pathways were involved in mediating the estrogenic actions of Rg1 in MCF-7 cells in comparison to 17beta-estradiol and estren. 17beta-estradiol decreased ERalpha protein expression in MCF-7 cells, but not Rg1 and estren. 17beta-estradiol increased ERalpha Ser 118 phosphorylation both in the cytoplasm and nucleus, especially in the nucleus. Rg1 increased ERalpha Ser 118 phosphorylation principally in the cytoplasm. Estren increased ERalpha Ser 118 phosphorylation pricipally in the nucleus. For the estrogen-related pS2 gene expression, both 17beta-estradiol and Rg1 increased pS2 mRNA expression in MCF-7 cells, while estren decreased pS2 mRNA expression. Additionally, both 17beta-estradiol and Rg1 induced the recruitment of co-activator SRC-1 to ERE-containing pS2 promoter, but not estren. Furthermore, we are the first to report the possible involvement of GPR30 pathway on the activation of MEK1/2 by Rg1 in MCF-7 cells.;In conclusion, the estrogenic effects of Rg1 might be tissue selective. The rapid ER-dependent signaling pathway was involved in the tissue-selective estrogenic effects of Rg1. |
