Activation of insulin-like growth factor I receptor-mediated pathway by ginsenoside Rg1.
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. Rg1 (1 pM) stimulates cell proliferation (P<0.01) and estrogen-responsive pS2 mRNA expression (P<0.05) without alteration of estrogen receptor alpha (ERalpha) protein or mRNA expression in MCF-7 cells. In addition, 10(-14)-10(-4) M of Rg1 does not demonstrate specific binding to ERalpha. 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. 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 muM of estrogen antagonist ICI 182,780 completely abolishes the effects of Rg1 on IGF-IR expression.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. 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.
Chen
Wen-Fang
WF
Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, People's Republic of China.
Lau
Wai-Sum
WS
Cheung
Pik-Yuen
PY
Guo
De-An
DA
Wong
Man-Sau
MS
D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000502:physiology; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics
D047628:Estrogen Receptor alpha; D036145:Ginsenosides; D012333:RNA, Messenger; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C035054:ginsenoside Rg1