Holothurian glycosaminoglycan inhibits metastasis via inhibition of P-selectin in B16F10 melanoma cells
Holothurian glycosaminoglycan inhibits metastasis via inhibition of P-selectin in B16F10 melanoma cells
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DOI：
10.1007/s11010-015-2546-4
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发表时间：
2015-08
影响因子：
4.3
通讯作者：
Zhi-qiang Yue;Aiyun Wang;Zhijie Zhu;L. Tao;Yao Li;Liang Zhou;Wenxing Chen;Yin Lu
中科院分区：
文献类型：
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作者：
Zhi-qiang Yue;Aiyun Wang;Zhijie Zhu;L. Tao;Yao Li;Liang Zhou;Wenxing Chen;Yin Lu
P-选择素介导的肿瘤细胞与血小板的粘附是肿瘤转移过程中的一个公认阶段。通过计算机结构分析，我们发现一种海洋来源的多糖，海参糖胺聚糖（hGAG），表现为P-选择素的配体竞争性抑制剂，这表明它有可能破坏P-选择素与细胞表面受体的结合，并激活肿瘤细胞迁移的下游调节因子。我们的实验数据表明，hGAG显着抑制P-选择素介导的粘附肿瘤细胞的血小板和肿瘤细胞的迁移在体外，并减少随后的肺转移在体内。此外，P-选择素介导的肿瘤细胞粘附的消除导致B16 F10细胞中整合素、FAK和MMP-2/9的蛋白水平下调，这是hGAG抑制肿瘤转移的关键分子机制。总之，hGAG已成为一种新型的抗癌剂，通过阻断P-选择素介导的恶性肿瘤转移事件。
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.