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L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor

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Abstract

The L1CAM cell adhesion/recognition molecule (L1, CD171) and fibroblast growth factor receptor (FGFR) both are expressed by human high-grade glioma cells, but their potential actions in controlling cell behavior have not been linked. L1 actions in cancer cells have been attributed mainly to integrin receptors, and we demonstrated previously that L1-stimulated glioma cell migration correlates with integrin expression, increased focal adhesion kinase activation and focal complex turnover. Our analyses of datasets revealed FGFR is overexpressed in glioma regardless of grade, while ADAM10 metalloprotease expression increases with glioma grade. Here, we used dominant-negative and short hairpin RNA approaches to inhibit the activation of FGFR1 and expression of L1, respectively. An L1 peptide that inhibits L1-FGFR interaction and PD173074, a chemical inhibitor of FGFR1 activity, also were used to elucidate the involvement of L1-FGFR interactions on glioma cell behavior. Time-lapse cell motility studies and flow cytometry cell cycle analyses showed that L1 operates to increase glioma cell motility and proliferation through FGFR activation. Shutdown of both L1 expression and FGFR activity in glioma cells resulted in a complete termination of cell migration in vitro. These studies show for the first time that soluble L1 ectodomain (L1LE) acts on glioma cells through FGFRs, and that FGFRs are used by glioma cells for increasing motility as well as proliferation in response to activation by L1LE ligand. Thus, effective treatment of high-grade glioma may require simultaneous targeting of L1, FGFRs, and integrin receptors, which would reduce glioma cell motility as well as proliferation.

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Abbreviations

FGFR:

Fibroblast growth factor receptor

L1LE:

L1 long ectodomain

GBM:

Glioblastoma multiforme

FN:

Fibronectin-like repeats

CAMs:

Cell adhesion molecules

CHD:

CAM homology domains

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Acknowledgments

The authors would like to thank Dr. Elena Pasquale at the Sanford Burnham Medical Research Institute for the cek-1 plasmid. This work was funded by grant Number 2 P20 RR016472 under the INBRE program of the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and by research resources of the Genetically Defined Microbe and Expression Core of the UAB Mucosal HIV and Immunobiology Center (R24 DK64400).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

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

    Vishnu Mohanan & Deni S. Galileo

  2. Department of Biological Sciences, Delaware State University, Dover, DE, 19901

    Murali K. Temburni

  3. Department of Medicine, University of Alabama, Birmingham, AL, 35294

    John C. Kappes

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  1. Vishnu Mohanan
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  2. Murali K. Temburni
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  4. Deni S. Galileo
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Correspondence to Deni S. Galileo.

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Mohanan, V., Temburni, M.K., Kappes, J.C. et al. L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor. Clin Exp Metastasis 30, 507–520 (2013). https://doi.org/10.1007/s10585-012-9555-4

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