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Ginsenoside Rb1 inhibits tube‐like structure formation of endothelial cells by regulating pigment epithelium‐derived factor through the oestrogen β receptor
Author(s) -
Leung K W,
Cheung L W T,
Pon Y L,
Wong R N S,
Mak N K,
Fan TPD,
Au S C L,
TombranTink J,
Wong A S T
Publication year - 2007
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0707359
Subject(s) - pedf , angiogenesis , transfection , microbiology and biotechnology , receptor , chemistry , biology , agonist , cancer research , endocrinology , biochemistry , gene
Background and purpose: Angiogenesis is a crucial step in tumour growth and metastasis. Ginsenoside‐Rb1 (Rb1), the major active constituent of ginseng, potently inhibits angiogenesis in vivo and in vitro . However, the underlying mechanism remains unknown. We hypothesized that the potent anti‐angiogenic protein, pigment epithelium‐derived factor (PEDF), is involved in regulating the anti‐angiogenic effects of Rb1. Experimental approaches: Rb1‐induced PEDF was determined by real‐time PCR and western blot analysis. The anti‐angiogenic effects of Rb1 were demonstrated using endothelial cell tube formation assay. Competitive ligand‐binding and reporter gene assays were employed to indicate the interaction between Rb1 and the oestrogen receptor (ER). Key results: Rb1 significantly increased the transcription, protein expression and secretion of PEDF. Targeted inhibition of PEDF completely prevented Rb1‐induced inhibition of endothelial tube formation, suggesting that the anti‐angiogenic effect of Rb1 was PEDF specific. Interestingly, the activation of PEDF occurred via a genomic pathway of ER β . Competitive ligand‐binding assays indicated that Rb1 is a specific agonist of ER β , but not ER α . Rb1 effectively recruited transcriptional activators and activated an oestrogen‐responsive reporter gene. Furthermore, Rb1‐mediated PEDF activation and the subsequent inhibition of tube formation were blocked by the ER antagonist ICI 182,780 or transfection of ER β siRNA, indicating ER β dependence. Conclusions and implications: Here we show for the first time that the Rb1 suppressed the formation of endothelial tube‐like structures through modulation of PEDF via ER β . These findings demonstrate a novel mechanism of the action of this ginsenoside that may have value in anti‐cancer and anti‐angiogenesis therapy. British Journal of Pharmacology (2007) 152 , 207–215; doi: 10.1038/sj.bjp.0707359