title: Ginsenoside compound K inhibits angiogenesis via regulation of sphingosine kinase-1 in human umbilical vein endothelial cells.
abstract: Ginsenoside compound K (CK) is a metabolite of the protopanaxadiol-type saponins of Panax ginseng C.A. Meyer (Araliaceae), has long been used to treat against the development of cancer, inflammation, allergies, and diabetes. This study examined the anti-angiogenic properties of CK against sphingosine 1-phosphate (S1P)-induced cell migration via regulation of sphingosine kinase 1 (SPHK1) in human umbilical vein endothelial cells (HUVEC). Studies on S1P-induced cell migration, expression of SPHK1 and MMPs and analysis of sphingolipid metabolites by LC-MS/MS were examined after the treatment of CK (2.5, 5, 10 μg/mL) in HUVEC. S1P produced by SPHK1 is also involved in cell growth, migration, and protection of apoptosis; therefore, we sought to investigate whether ginsenosides are able to regulate SPHK1. For this purpose, we developed an inhibitory assay of SPHK1 activity and an analytical method for detection of S1P and other sphingolipid metabolites in HUVEC. Ginsenoside CK inhibited 100 nM S1P-induced cell migrations in a dose-dependent manner. Among tested ginsenosides, CK exclusively inhibited S1P production, SPHK1 activity and SPHK1 expression in HUVEC, whereas expression of the pro-apoptotic sphingolipids, sphingosine and ceramide, was increased in response to CK. The major subspecies of the increased ceramide was C24:0-ceramide. CK also disrupted the sphingolipid rheostat, which ultimately influences cell fate, and dose-dependently inhibited HUVEC migration by reducing expression of metalloproteinases (MMPs). Ginsenoside CK acts as a unique HUVEC migration inhibitor by regulating MMP expression, as well as the activity of SPHK1 and its related sphingolipid metabolites.
authors.affiliation: College of Pharmacy and MRC, Chungbuk National University, Cheongju, 361-763, Korea.
authors.forename: Kyong-Oh
authors.initials: KO
authors.lastname: Shin
authors.forename: Cho-Hee
authors.initials: CH
authors.lastname: Seo
authors.forename: Hyo-Hyun
authors.initials: HH
authors.lastname: Cho
authors.forename: Seikwan
authors.initials: S
authors.lastname: Oh
authors.forename: Seon-Pyo
authors.initials: SP
authors.lastname: Hong
authors.forename: Hwan-Soo
authors.initials: HS
authors.lastname: Yoo
authors.forename: Jin-Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Ki-Wan
authors.initials: KW
authors.lastname: Oh
authors.forename: Yong-Moon
authors.initials: YM
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000819:agonists / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D036145:Ginsenosides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D020533:Angiogenesis Inhibitors; D016588:Anticarcinogenic Agents; D002518:Ceramides; D004791:Enzyme Inhibitors; D036145:Ginsenosides; D008246:Lysophospholipids; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C112772:ginsenoside compound K; C522361:MMP2 protein, human; C579270:MMP9 protein, human