A synthetic glycosphingolipid-induced antiproliferative effect in melanoma cells is associated with suppression of FAK, Akt, and Erk activation
A synthetic glycosphingolipid-induced antiproliferative effect in melanoma cells is associated with suppression of FAK, Akt, and Erk activation
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DOI：
10.1248/bpb.31.1279
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发表时间：
2008-06-01
影响因子：
2
通讯作者：
Kasahara, Tadashi
中科院分区：
文献类型：
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作者：
Sonoda, Yoshiko;Hada, Noriyasu;Kasahara, Tadashi
大量研究表明，糖脂参与信号转导，调节黑色素瘤细胞的生长和凋亡。为了发现新的抗癌药物，我们合成了十种在各种无脊椎动物中发现的不含唾液酸的糖脂。测试这些化合物对黑素瘤细胞系B16 F10的抗增殖作用。在千足虫Parafontaria laminata armigera中鉴定的一种合成化合物Man beta（1-4）[Fuc alpha（1-3）]Glc beta 1-Cer（鞘糖脂7）对黑色素瘤细胞具有抗增殖作用。该化合物抑制粘着斑激酶（FAK）-Akt通路的激活以及参与细胞增殖的细胞外信号调节激酶（Erk）1/2通路的激活。细胞周期蛋白，细胞周期蛋白D1和CDK 4的表达，被鞘糖脂7抑制。根据这些结果，鞘糖脂7抑制FAK-Akt通路和Erk 1/2的活化，这导致细胞周期蛋白D1和CDK 4的表达减少。鞘糖脂7可能是黑色素瘤细胞增殖抑制剂的候选者。
Numerous studies have demonstrated the participation of glicolipids in signal transduction and the regulation of melanoma cell growth and apoptosis. Hoping to discover new anticancer drugs, we have synthesized ten glycolipids found in various invertebrates that do not have sialic acids. These compounds were tested for antiproliferative effects on a melanoma cell line, B16F10. A synthetic compound, Man beta(1-4)[Fuc alpha(1-3)]Glc beta 1-Cer, (glycosphingolipid 7), which,vas identified in the millipede Parafontaria laminata armigera, had an antiproliferative effect on the melanoma cells. This compound suppressed the activation of the focal adhesion kinase (FAK)-Akt pathway as well as the activation of extracellular signal-regulated kinase (Erk)1/2 pathway involved in cell proliferation. Expression of the cell cycle proteins, cyclin D1 and CDK4, was suppressed by glycosphingolipid 7. From these results, glycosphingolipid 7 suppressed the activation of the FAK-Akt pathway and of Erk1/2, which resulted in a decrease in the expression of cyclin D1 and CDK4. Glycosphingolipid 7 might be a candidate for an inhibitor of cell proliferation in melanomas.