CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer.
CXCR4 antagonist inhibits stromal cell-derived factor 1-induced migration and invasion of human pancreatic cancer.
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DOI：
10.1158/1535-7163.29.3.1
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发表时间：
2004-01
影响因子：
5.7
通讯作者：
Tomohiko Mori;R. Doi;M. Koizumi;E. Toyoda;D. Ito;K. Kami;T. Masui;K. Fujimoto;H. Tamamura;K. Hiramatsu;N. Fujii;M. Imamura
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文献类型：
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作者：
Tomohiko Mori;R. Doi;M. Koizumi;E. Toyoda;D. Ito;K. Kami;T. Masui;K. Fujimoto;H. Tamamura;K. Hiramatsu;N. Fujii;M. Imamura
基质细胞衍生因子-1（SDF-1）/CXCR 4系统参与哺乳动物细胞迁移的各种情况，包括淋巴细胞的迁移和转移的形成。我们最近合成了一种有效的新型CXCR 4拮抗剂TN 14003。本研究旨在探讨SDF-1/CXCR 4轴在胰腺癌细胞迁移和侵袭转移中的作用，以及TN 14003对胰腺癌细胞转移的抑制作用。采用Western blotting和免疫细胞化学方法检测6株胰腺癌细胞系中CXCR 4的表达。在迁移和侵袭测定中，SDF-1以剂量依赖性方式刺激癌细胞的迁移和侵袭。在100 ng/ml时观察到SDF-1的最大作用。SDF-1诱导的癌细胞迁移和侵袭被100 nM TN 14003完全阻断。SDF-1对癌细胞迁移的刺激作用和TN 14003的抑制作用是通过改变丝裂原活化蛋白激酶的磷酸化来介导的。用100 ng/ml SDF-1处理癌细胞导致肌动蛋白聚合的显著增加，100 nM TN 14003降低了肌动蛋白聚合。SDF-1增强癌细胞与层粘连蛋白的粘附，TN 14003不能逆转这种粘附。综上所述，SDF-1/CXCR 4轴通过迁移和侵袭参与胰腺癌转移。CXCR 4的小分子拮抗剂TN 14003可能是一种有效的抗胰腺癌转移药物。
The stromal cell-derived factor-1 (SDF-1)/CXCR4 system is implicated in various instances of cell migration in mammals, including the migration of lymphocytes and the formation of metastases. We have recently synthesized a potent novel CXCR4 antagonist, TN14003. The purpose of this study was to investigate the role of SDF-1/CXCR4 axis in the pancreatic cancer metastasis via cell migration and invasion, and the inhibitory effect of TN14003 on pancreatic cancer cell metastasis. The expression of CXCR4 was detected in six pancreatic cancer cell lines by Western blotting and immunocytochemistry. In migration and invasion assays, SDF-1 stimulated both migration and invasion of cancer cells in a dose-dependent manner. The maximal effect of SDF-1 was observed at 100 ng/ml. SDF-1-induced migration and invasion of cancer cells were completely blocked by 100 nM TN14003. The stimulatory effect of SDF-1 on cancer migration and the inhibitory effect of TN14003 were mediated via the alteration in phosphorylation of mitogen-activated protein kinases. Treatment of cancer cells with 100 ng/ml SDF-1 resulted in a significant increase of actin polymerization, which was reduced by 100 nM TN14003. SDF-1 enhanced cancer cell adhesion to laminin, which was not reversed by TN14003. Taken together, SDF-1/CXCR4 axis is involved in pancreatic cancer metastasis through migration and invasion. The small molecule antagonists against CXCR4 such as TN14003 might be an effective anti-metastatic agent for pancreatic cancer.