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Holothurian glycosaminoglycan inhibits metastasis via inhibition of P-selectin in B16F10 melanoma cells

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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.

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Acknowledgments

This Project was supported in part by National Natural Science Foundation of China (Nos. 81173174, 81202655), Doctoral Program of the Ministry of Education (20113237110008), 2013’ Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education, Jiangsu Ordinary University Graduate Students Scientific Research Innovation Program (CXLX11-0772), and a project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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    Authors and Affiliations

    1. College of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, Jiangsu, China

      Zhiqiang Yue, Aiyun Wang, Zhijie Zhu, Li Tao, Yao Li, Liang Zhou, Wenxing Chen & Yin Lu

    2. Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing, 210023, China

      Aiyun Wang, Wenxing Chen & Yin Lu

    3. Jiangsu Provincial Center for Research and Development of Marine Drugs, Nanjing, 210023, Jiangsu, China

      Aiyun Wang, Wenxing Chen & Yin Lu

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    1. Zhiqiang Yue
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    Zhiqiang Yue and Aiyun Wang have contributed equally to this work.

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    Supplementary Fig. 1

    Plot of hGAG interaction between TGF-β (a), PDGF-B (b), TNF-α (c), vWF (d), ADP (e), Platelet factor 4 (f), GPIIb/IIIa (g), Thrombin (h) and Thromboxane A2 (i). hGAG is shown in ball and stick fashion, putative hydrogen bonds are shown as green dashed lines, and residues involved in hydrogen bond formation are shown in flat lines

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    Yue, Z., Wang, A., Zhu, Z. et al. Holothurian glycosaminoglycan inhibits metastasis via inhibition of P-selectin in B16F10 melanoma cells. Mol Cell Biochem 410, 143–154 (2015). https://doi.org/10.1007/s11010-015-2546-4

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