L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor
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RESEARCH PAPER
L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor Vishnu Mohanan • Murali K. Temburni John C. Kappes • Deni S. Galileo
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Received: 21 May 2012 / Accepted: 17 November 2012 / Published online: 1 December 2012 Ó Springer Science+Business Media Dordrecht 2012
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 dominantnegative 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. Keywords Glioma Glioblastoma FGFR L1CAM Cell Motility Cell Proliferation 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
Electronic supplementary material The online version of this article (doi:10.1007/s10585-012-9555-4) contains supplementary material, which is available to authorized users. V. Mohanan D. S. Galileo (&) Department of Biological Sciences, University of Delaware, Newark, DE 19716 e-mail: [email protected] M. K. Temburni Department of Biological Sciences, Delaware State University, Dover, DE 19901 J. C. Kappes Department of Medicine, University of Alabama, Birmingham, AL 35294
Introduction Glioblastoma multiforme (GBM) is one of the most common types of adult brain tumor [1–3] and currently has no successful treatment. Surgery remains the primary treatment, but because cells tend to migrate into brain parenchyma, they invariably escape resection. Adj
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