Authors: Adriana EstradaBernal Sean E Lawler Michal O Nowicki Abhik Ray Chaudhury James R Van Brocklyn
Publish Date: 2010/10/12
Volume: 102, Issue: 3, Pages: 353-366
Abstract
We have previously shown that high expression levels of the lipid kinase sphingosine kinase1 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 EGFRvIIIinduced 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 GBMderived neurosphere cell line GBM9 which forms GBMlike 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 GBMderived neurosphere cells and EGFRvIII partially utilizes SphK1 to further enhance cell proliferationThe authors are grateful to Dr Amyn Habib of the University of Texas Southwestern Medical Center for the gift of U251E18 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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