Abstract
P-selectin-mediated tumor cell adhesion to platelets is a well-established stage in the process of tumor metastasis. Through computerized structural analysis, we found a marine-derived polysaccharide, holothurian glycosaminoglycan (hGAG), behaved as a ligand-competitive inhibitor of P-selectin, indicating its potential to disrupt the binding of P-selectin to cell surface receptor and activation of downstream regulators of tumor cell migration. Our experimental data demonstrated that hGAG significantly inhibited P-selectin-mediated adhesion of tumor cells to platelets and tumor cell migration in vitro and reduced subsequent pulmonary metastasis in vivo. Furthermore, abrogation of the P-selectin-mediated adhesion of tumor cells led to down-regulation of protein levels of integrins, FAK and MMP-2/9 in B16F10 cells, which is a crucial molecular mechanism of hGAG to inhibit tumor metastasis. In conclusion, hGAG has emerged as a novel anti-cancer agent via blocking P-selectin-mediated malignant events of tumor metastasis.
Keywords:
Holothurian glycosaminoglycan; Melanoma; P-Selectin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / isolation & purification
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Movement / drug effects*
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Dose-Response Relationship, Drug
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Female
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Focal Adhesion Kinase 1 / metabolism
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Glycosaminoglycans / chemistry
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Glycosaminoglycans / isolation & purification
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Glycosaminoglycans / metabolism
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Glycosaminoglycans / pharmacology*
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Holothuria* / chemistry
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Integrins / metabolism
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / prevention & control*
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Lung Neoplasms / secondary
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / metabolism
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Melanoma, Experimental / drug therapy*
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Melanoma, Experimental / genetics
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / secondary
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Mice, Inbred C57BL
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Molecular Docking Simulation
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Neoplasm Invasiveness
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P-Selectin / antagonists & inhibitors*
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P-Selectin / chemistry
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P-Selectin / genetics
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P-Selectin / metabolism
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Protein Binding
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Protein Conformation
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Signal Transduction / drug effects
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Zebrafish
Substances
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Antineoplastic Agents
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Glycosaminoglycans
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Integrins
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P-Selectin
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Focal Adhesion Kinase 1
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Ptk2 protein, mouse
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Matrix Metalloproteinase 2
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Mmp2 protein, mouse
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Matrix Metalloproteinase 9
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Mmp9 protein, mouse