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1 Ginsenoside Rg1, an active ingredient in ginseng, was previously shown to be a novel class of potent phytoestrogen. The present study aims at investigating the molecular mechanisms involved in mediating its actions in human breast cancer (MCF-7) cells. 2 Rg1 (1 pM) stimulates cell proliferation (Po0.01) and estrogen-responsive pS2 mRNA expression (Po0.05) without alteration of estrogen receptor alpha (ERa) protein or mRNA expression in MCF-7 cells. In addition, 10 À14 -10 À4 M of Rg1 does not demonstrate specific binding to ERa.3 We hypothesize that Rg1 may exert its actions in MCF-7 cell via the activation of crosstalk between ER-and insulin growth factor I receptor (IGF-IR)-dependent pathways. 4 The results indicate that Rg1 significantly increases IGF-IR expression and IGF-IR promoter activity in MCF-7 cells (Po0.05). Cotreatment of MCF-7 cells with 1 mM of estrogen antagonist ICI 182,780 completely abolishes the effects of Rg1 on IGF-IR expression. 5 Furthermore, Rg1 enhances tyrosine phosphorylation of IRS-1 in MCF-7 cells upon IGF-I stimulation and the activation of IRS-1 phosphorylation is also ER-dependent. 6 Taken together, our results suggest that Rg1 not only increases IGF-IR expression but also enhances IGF-IR-mediated signaling pathways in MCF-7 cells. The stimulation of IGF-IR expression by Rg1 in MCF-7 cells appears to require ER, and its actions might involve ligand-independent activation of ER.

Our previous studies have demonstrated that ginsenoside Rg1 is a novel class of potent phytoestrogen and can mimic the action of estradiol in stimulation of MCF‐7 cell growth by the crosstalk between insulin‐like growth factor‐I receptor (IGF‐IR)‐dependent pathway and estrogen receptor (ER)‐dependent pathway. The present study was designed to investigate the neuroprotective effects of ginsenoside Rg1 against 6‐hydroxydopamine (6‐OHDA)‐induced neurotoxicity in human neuroblastoma SK‐N‐SH cells and the possible mechanisms. Pre‐treatment with ginsenoside Rg1 resulted in an enhancement of survival, and significant rescue occurred at the concentration of 0.01 μM on cell viability against 6‐OHDA‐induced neurotoxicity. These effects could be completely blocked by IGF‐IR antagonist JB‐1 or ER antagonist ICI 182780. 6‐OHDA arrested the cells at G0G1 phase and prevented S phase entry. Rg1 pre‐treatment could reverse the cytostatic effect of 6‐OHDA. Ginsenoside Rg1 also could attenuate 6‐OHDA‐induced decrease in mitochondrial membrane potential. These effects could also be completely blocked by JB‐1 or ICI 182780. Furthermore, 6‐OHDA‐induced up‐regulation of Bax and down‐regulation of Bcl‐2 mRNA and protein expression could be restored by Rg1 pre‐treatment. Rg1 pre‐treatment could reverse the down‐regulation of ERα protein expression induced by 6‐OHDA treatment. Cells transfected with the estrogen responsive element (ERE)‐luciferase reporter construct exhibited significantly increased ERE‐luciferase activity in the Rg1 presence, suggesting that the estrogenic effects of Rg1 were mediated through the endogenous ERs. These results suggest that ginsenoside Rg1 may attenuate 6‐OHDA‐induced apoptosis and its action might involve the activation of IGF‐IR signaling pathway and ER signaling pathway.