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Small-molecule inhibitors of FGFR, integrins and FAK selectively decrease L1CAM-stimulated glioblastoma cell motility and proliferation

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Abstract

Purpose

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.

Methods

The effects of the FGFR inhibitor PD173074, the FAK inhibitors PF431396 and Y15 and the αvβ3/αvβ5 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.

Results

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.

Conclusions

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.

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Acknowledgments

This work was funded by the Delaware Bioscience Center for Advanced Technology and by the University of Delaware Undergraduate Research Program. H. J. Anderson was supported by the Delaware INBRE program, supported by a grant from the National Institute of General Medical Sciences—NIGMS (P20 GM103446) from the National Institutes of Health, and by the Delaware Governor’s Bioscience Fellowship. The authors thank Dr. Vishnu Mohanan for critically reading the manuscript.

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  1. Department of Biological Sciences, University of Delaware, Newark, DE, 19716, USA

    Hannah J. Anderson & Deni S. Galileo

  2. Helen F. Graham Cancer Center and Research Institute, Christiana Care Health System, Newark, DE, 19713, USA

    Deni S. Galileo

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Anderson, H.J., Galileo, D.S. Small-molecule inhibitors of FGFR, integrins and FAK selectively decrease L1CAM-stimulated glioblastoma cell motility and proliferation. Cell Oncol. 39, 229–242 (2016). https://doi.org/10.1007/s13402-016-0267-7

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