Small-molecule inhibitors of FGFR, integrins and FAK selectively decrease L1CAM-stimulated glioblastoma cell motility and proliferation
Small-molecule inhibitors of FGFR, integrins and FAK selectively decrease L1CAM-stimulated glioblastoma cell motility and proliferation
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DOI：
10.1007/s13402-016-0267-7
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发表时间：
2016-06-01
影响因子：
6.6
通讯作者：
Galileo, Deni S.
中科院分区：
文献类型：
--
作者：
Anderson, Hannah J.;Galileo, Deni S.
细胞粘附/识别蛋白L1CAM （L1; CD171）先前已被证明通过整合素、局点粘附激酶（FAK）和成纤维细胞生长因子受体（FGFR）信号通路起作用，以自分泌/旁分泌的方式增加胶质母细胞瘤细胞的运动和增殖。在这里，我们研究了临床相关的整合素、FAK和FGFR信号通路小分子抑制剂对胶质母细胞瘤来源细胞的影响，以确定它们在减少l1介导的刺激方面的有效性和选择性。研究了FGFR抑制剂PD173074、FAK抑制剂PF431396和Y15以及α v β 3/ α v β 5整合素抑制剂西伦吉肽对人胶质母细胞瘤来源细胞系T98G和U-118 MG的l1阳性和l1阴性变体的影响。分别用延时显微镜和DNA含量/细胞周期分析来量化它们的运动性和增殖。所有四种抑制剂的应用导致l1介导的胶质母细胞瘤衍生细胞的运动和增殖率降低，当使用纳摩尔浓度时降至l1阴性细胞的水平，而在l1阴性细胞中没有或更小程度地降低这些速率。此外，我们发现单一抑制剂治疗效果最大（即FAK或整合素抑制剂与FGFR抑制剂联合使用很少更有效）。这些结果表明FAK可能在这些细胞中作为L1刺激的整合素和FGFR信号通路之间的会聚点。我们在这里首次表明FGFR、整合素和FAK的小分子抑制剂有效和选择性地消除l1刺激的胶质母细胞瘤来源细胞的迁移和增殖。我们的研究结果表明，这些抑制剂有可能降低表达L1的高级别胶质瘤的侵袭性。
The cell adhesion/recognition protein L1CAM (L1; CD171) has previously been shown to act through integrin, focal adhesion kinase (FAK) and fibroblast growth factor receptor (FGFR) signaling pathways to increase the motility and proliferation of glioblastoma cells in an autocrine/paracrine manner. Here, we investigated the effects of clinically relevant small-molecule inhibitors of the integrin, FAK and FGFR signaling pathways on glioblastoma-derived cells to determine their effectiveness and selectivity for diminishing L1-mediated stimulation.The effects of the FGFR inhibitor PD173074, the FAK inhibitors PF431396 and Y15 and the alpha v beta 3/alpha v beta 5 integrin inhibitor cilengitide were assessed in L1-positive and L1-negative variants of the human glioblastoma-derived cell lines T98G and U-118 MG. Their motility and proliferation were quantified using time-lapse microscopy and DNA content/cell cycle analyses, respectively.The application of all four inhibitors resulted in reductions in L1-mediated motility and proliferation rates of L1-positive glioblastoma-derived cells, down to the level of L1-negative cells when used at nanomolar concentrations, whereas no or much smaller reductions in these rates were obtained in L1-negative cells. In addition, we found that single inhibitor treatment resulted in maximum effects (i.e., combinations of FAK or integrin inhibitors with the FGFR inhibitor were rarely more effective). These results suggest that FAK may act as a point of convergence between the integrin and FGFR signaling pathways stimulated by L1 in these cells.We here show for the first time that small-molecule inhibitors of FGFR, integrins and FAK effectively and selectively abolish L1-stimulated migration and proliferation of glioblastoma-derived cells. Our results suggest that these inhibitors have the potential to reduce the aggressiveness of high-grade gliomas expressing L1.