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The role of sphingosine kinase-1 in EGFRvIII-regulated growth and survival of glioblastoma cells

  • Laboratory Investigation - Human/Animal Tissue
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Abstract

We have previously shown that high expression levels of the lipid kinase sphingosine kinase-1 (SphK1) correlate with poor survival of glioblastoma (GBM) patients. In this study we examined the regulation of SphK1 expression by epidermal growth factor receptor (EGFR) signaling in GBM cells. As the EGFR gene is often overexpressed and mutated in GBM, and EGFR has been shown to regulate SphK1 in some cell types, we examined the effect of EGF signaling and the constitutively active EGFRvIII mutant on SphK1 in GBM cells. Treatment of glioma cell lines with EGF led to increased expression and activity of SphK1. Expression of EGFRvIII in glioma cells also activated and induced SphK1. In addition, siRNA to SphK1 partially inhibited EGFRvIII-induced growth and survival of glioma cells as well as ERK MAP kinase activation. To further evaluate the connection between EGFR and SphK1 in GBM we examined primary neurosphere cells isolated from fresh human GBM tissue. The GBM-derived neurosphere cell line GBM9, which forms GBM-like tumors intracranially in nude mice, maintained expression of EGFRvIII in culture and had high levels of SphK1 activity. EGFR inhibitors modestly decreased SphK1 activity and proliferation of GBM9 cells. More extensive blockage of SphK1 activity by a SphK inhibitor, potently blocked cell proliferation and induced apoptotic cell death of GBM9 cells. Thus, SphK1 activity is necessary for survival of GBM-derived neurosphere cells, and EGFRvIII partially utilizes SphK1 to further enhance cell proliferation.

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Acknowledgments

The authors are grateful to Dr. Amyn Habib of the University of Texas Southwestern Medical Center for the gift of U251-E18 cells, and to Dr. Lina Obeid of the Medical University of South Carolina for the gift of the SphK1 promoter luciferase construct. This work was supported by Grant # R21CA124685 from the National Cancer Institute (NCI) to JRVB and by the Department of Pathology, The Ohio State University.

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Authors and Affiliations

  1. Department of Pathology, The Ohio State University, 4164 Graves Hall, 333 W. 10th Ave., Columbus, OH, 43210, USA

    Adriana Estrada-Bernal, Abhik Ray Chaudhury & James R. Van Brocklyn

  2. Department of Neurosurgery, The Ohio State University, Columbus, OH, USA

    Sean E. Lawler & Michal O. Nowicki

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  1. Adriana Estrada-Bernal
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  2. Sean E. Lawler
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  3. Michal O. Nowicki
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  4. Abhik Ray Chaudhury
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  5. James R. Van Brocklyn
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Correspondence to James R. Van Brocklyn.

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Estrada-Bernal, A., Lawler, S.E., Nowicki, M.O. et al. The role of sphingosine kinase-1 in EGFRvIII-regulated growth and survival of glioblastoma cells. J Neurooncol 102, 353–366 (2011). https://doi.org/10.1007/s11060-010-0345-z

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  • DOI: https://doi.org/10.1007/s11060-010-0345-z

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