Activation of insulin-like growth factor I receptor-mediated pathway by ginsenoside Rg1

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 (P<0.01) and estrogen-responsive pS2 mRNA expression (P<0.05) without alteration of estrogen receptor alpha (ER alpha) protein or mRNA expression in MCF-7 cells. In addition, 10(-1)4 - 10(-4) M of Rg1 does not demonstrate specific binding to ER alpha. 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 (P<0.05). Cotreatment of MCF-7 cells with 1 mu M 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.