Mitogen-activated protein kinase (MAPK) pathway mediates the oestrogen-like activities of ginsenoside Rg1 in human breast cancer (MCF-7) cells.
OBJECTIVE
The present study was designed to determine how ginsenoside Rg1, an active ingredient in ginseng root, exerts its oestrogenic effects. We hypothesize that Rg1 may exert oestrogen-like actions in MCF-7 cells by activating the mitogen-activated protein kinase (MAPK) pathway in a ligand-independent manner.


METHODS
MCF-7 cells were co-incubated with the MAPK inhibitor PD98059 to determine whether the stimulant effects of Rg1 on cell proliferation, the induction of IGF-IR and pS2, the functional transactivation of oestrogen receptor-alpha (ERalpha), as well as ERalpha phosphorylation are dependent on MAPK. The time-dependent responses of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated protein kinase (ERK) to Rg1 in MCF-7 cells were studied. The responses of MEK phosphorylation to Rg1 in oestrogen receptor (ER)-negative HEK293 cells were also determined. The effects of Rg1 on cell proliferation and IGF-IR protein expression were studied in the presence of tyrosine kinase inhibitor genistein to elucidate the involvement of tyrosine kinase in mediating these effects.


RESULTS
The oestrogenic effects of Rg1 in MCF-7 cells were abolished in the presence of PD98059. Rg1 could induce MEK protein expression and the phosphorylation level of MEK and ERK significantly in a time- and dose-dependent manner. Rg1 activated MEK phosphorylation in ER-negative HEK293 cells in a time- and dose-dependent manner. Rg1 induction of cell proliferation and IGF-IR protein expression was abolished by co-treatment with genistein.


CONCLUSIONS
Taken together, these results show that the MAPK pathway is involved in mediating the oestrogen-like actions of Rg1 in MCF-7 cells and suggest that Rg1 may activate ERalpha via MEK/ERK in a ligand-independent manner.
Lau
Wai-Sum
WS
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, China.
Chen
Wen-Fang
WF
Chan
Robbie Yat-Kan
RY
Guo
De-An
DA
Wong
Man-Sau
MS
D001943:Breast Neoplasms; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis
D047628:Estrogen Receptor alpha; D004967:Estrogens; D005419:Flavonoids; D036145:Ginsenosides; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases; C035054:ginsenoside Rg1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one