Document Detail

The role of sphingosine kinase-1 in EGFRvIII-regulated growth and survival of glioblastoma cells.
MedLine Citation:
PMID:  20938717     Owner:  NLM     Status:  MEDLINE    
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.
Adriana Estrada-Bernal; Sean E Lawler; Michal O Nowicki; Abhik Ray Chaudhury; James R Van Brocklyn
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-12
Journal Detail:
Title:  Journal of neuro-oncology     Volume:  102     ISSN:  1573-7373     ISO Abbreviation:  J. Neurooncol.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-09     Completed Date:  2011-07-29     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  8309335     Medline TA:  J Neurooncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  353-66     Citation Subset:  IM    
Department of Pathology, The Ohio State University, 4164 Graves Hall, 333 W. 10th Ave., Columbus, OH 43210, USA.
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MeSH Terms
Annexin A5 / metabolism
Brain Neoplasms / mortality*,  pathology
Cell Line, Tumor
Cell Proliferation / drug effects*
Cell Survival / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Epidermal Growth Factor / pharmacology
Gene Expression Regulation, Neoplastic / drug effects,  physiology*
Glioblastoma / mortality*,  pathology
Mice, Nude
Mutation / genetics
Phosphotransferases (Alcohol Group Acceptor) / genetics,  metabolism*
RNA, Small Interfering / pharmacology
Receptor, Epidermal Growth Factor / metabolism*
Signal Transduction / drug effects
Time Factors
Grant Support
R21 CA124685-02/CA/NCI NIH HHS; R21CA124685/CA/NCI NIH HHS
Reg. No./Substance:
0/Annexin A5; 0/RNA, Small Interfering; 0/epidermal growth factor receptor VIII; 62229-50-9/Epidermal Growth Factor; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase; EC, Epidermal Growth Factor

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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