title: Differential effects of sulfated triterpene glycosides, holothurin A1, and 24-dehydroechinoside A, on antimetastasic activity via regulation of the MMP-9 signal pathway.
abstract: Two sulfated triterpene glycosides, holothurin A(1) (HA(1)) and 24-dehydroechinoside A (DHEA), isolated from the sea cucumber Pearsonothuria graeffei, are of the holostane type with 18(20)-lactone and identical carbohydrate chains. DHEA has a side chain 23 (24)-double bond, while HA(1) has a hydroxyl group at C-21. In this study, we compared the effects of DHEA and HA(1) on metastasis in vitro and in vivo. The results show that HA(1) and DHEA treatment significantly suppressed adhesion of human hepatocellular liver carcinoma cells (HepG2) to both matrigel and human endothelial cells (ECV-304) and inhibited HepG2 cell migration and invasion in a dose-dependant manner. HA(1) and DHEA reduced tube formation of ECV-304 cells on the matrigel in vitro and attenuated neovascularization in the chick embryo using the chorioallantoic membrane (CAM) assay in vivo. Immunocytochemistry analyses revealed that both HA(1) and DHEA significantly decreased the expression of the matrix metallo-proteinase-9 (MMP-9) and increased the expression level of tissue inhibitor of metalloproteinase-1 (TIMP-1), an important regulator of MMP-9 activation. Western blot analyses demonstrated that HA(1) and DHEA remarkably abolished the expression of vascular endothelial growth factor (VEGF). The expression of nuclear factor-kappa B (NF-κB) was significantly decreased by HA(1), while DHEA treatment had no effect on the down regulation of NF-κB expression. These data suggest that both DHEA and HA(1) exert significant antimetastatic activities by inhibiting MMP-9 and VEGF expression. DHEA-induced antimetastasis was more potent than HA(1). In addition, only HA(1) treatment downregulated the expression level of NF-κB, suggesting that the antimetastatic activity of triterpene glycosides derived from P. graeffei can be either NF-κB-dependent or -independent, depending on their structure.
authors.affiliation: College of Food Science and Engineering, Ocean Univ. of China, Qingdao, Shandong Province, 266003, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhao
authors.forename: Yong
authors.initials: Y
authors.lastname: Xue
authors.forename: Zhi-dong
authors.initials: ZD
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Jing-feng
authors.initials: JF
authors.lastname: Wang
authors.forename: Zhao-jie
authors.initials: ZJ
authors.lastname: Li
authors.forename: Yu-ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Dong
authors.forename: Chang-hu
authors.initials: CH
authors.lastname: Xue
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000196:embryology; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006027:Glycosides / Q000494:pharmacology*; D056945:Hep G2 Cells; D006697:Holothurin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007797:Laminin / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011509:Proteoglycans / Q000187:drug effects / Q000378:metabolism; D012616:Sea Cucumbers / Q000737:chemistry; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014315:Triterpenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C560911:24-dehydroechinoside A; D000970:Antineoplastic Agents; D004338:Drug Combinations; D006027:Glycosides; D007797:Laminin; D016328:NF-kappa B; D011509:Proteoglycans; D019715:Tissue Inhibitor of Metalloproteinase-1; D014315:Triterpenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D006697:Holothurin; C059485:matrigel; C034723:holothurin A; D003094:Collagen; D020780:Matrix Metalloproteinase 9