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A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

The Journal of biological chemistry, 2013-12, Vol.288 (52), p.37355-37364 [Peer Reviewed Journal]

2013 © 2013 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2013 by The American Society for Biochemistry and Molecular Biology, Inc. 2013 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M113.494740 ;PMID: 24265321

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Title:
A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis
Author: Abuhusain, Hazem J. ; Matin, Azadeh ; Qiao, Qiao ; Shen, Han ; Kain, Nupur ; Day, Bryan W. ; Stringer, Brett W. ; Daniels, Benjamin ; Laaksonen, Maarit A. ; Teo, Charlie ; McDonald, Kerrie L. ; Don, Anthony S.
Subjects: Angiogenesis ; Angiogenesis Inhibitors - therapeutic use ; Animals ; Brain Neoplasms - drug therapy ; Brain Neoplasms - genetics ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Cancer ; Ceramide ; Ceramides - biosynthesis ; Ceramides - genetics ; Enzyme Inhibitors - therapeutic use ; Follow-Up Studies ; Glioblastoma ; Glioblastoma - drug therapy ; Glioblastoma - genetics ; Glioblastoma - metabolism ; Glioblastoma - pathology ; glioma ; Humans ; Lipid Metabolism ; Lipids ; Lysophospholipids - biosynthesis ; Lysophospholipids - genetics ; Male ; Membrane Proteins - antagonists & inhibitors ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Neovascularization, Pathologic - drug therapy ; Neovascularization, Pathologic - genetics ; Neovascularization, Pathologic - metabolism ; Neovascularization, Pathologic - pathology ; Phosphoric Monoester Hydrolases - antagonists & inhibitors ; Phosphoric Monoester Hydrolases - genetics ; Phosphoric Monoester Hydrolases - metabolism ; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors ; Phosphotransferases (Alcohol Group Acceptor) - genetics ; Phosphotransferases (Alcohol Group Acceptor) - metabolism ; Sphingolipid ; Sphingosine - analogs & derivatives ; Sphingosine - biosynthesis ; Sphingosine - genetics ; Sphingosine-1-Phosphate ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism
Is Part Of: The Journal of biological chemistry, 2013-12, Vol.288 (52), p.37355-37364
Description: Studies in cell culture and mouse models of cancer have indicated that the soluble sphingolipid metabolite sphingosine 1-phosphate (S1P) promotes cancer cell proliferation, survival, invasiveness, and tumor angiogenesis. In contrast, its metabolic precursor ceramide is prodifferentiative and proapoptotic. To determine whether sphingolipid balance plays a significant role in glioma malignancy, we undertook a comprehensive analysis of sphingolipid metabolites in human glioma and normal gray matter tissue specimens. We demonstrate, for the first time, a systematic shift in sphingolipid metabolism favoring S1P over ceramide, which increases with increasing cancer grade. S1P content was, on average, 9-fold higher in glioblastoma tissues compared with normal gray matter, whereas the most abundant form of ceramide in the brain, C18 ceramide, was on average 5-fold lower. Increased S1P content in the tumors was significantly correlated with increased sphingosine kinase 1 (SPHK1) and decreased sphingosine phosphate phosphatase 2 (SGPP2) expression. Inhibition of S1P production by cultured glioblastoma cells, using a highly potent and selective SPHK1 inhibitor, blocked angiogenesis in cocultured endothelial cells without affecting VEGF secretion. Our findings validate the hypothesis that an altered ceramide/S1P balance is an important feature of human cancers and support the development of SPHK1 inhibitors as antiangiogenic agents for cancer therapy. Background: The sphingolipid metabolite sphingosine 1-phosphate (S1P) is a potent angiogenic factor. Results: S1P content is 9-fold higher in glioblastomas compared with normal brain, and S1P production is necessary for glioblastoma cells to trigger endothelial cell angiogenesis. Conclusion: Excessive S1P synthesis is a major contributor to glioblastoma angiogenesis. Significance: Inhibiting S1P synthesis may be a valuable antiangiogenic approach in glioblastoma.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.M113.494740
PMID: 24265321
Source: PubMed Central (Open access)
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A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

2013 © 2013 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2013 by The American Society for Biochemistry and Molecular Biology, Inc. 2013 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M113.494740 ;PMID: 24265321

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