Abstract
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.
Keywords:
Angiogenesis; Cancer; Ceramide; Glioblastoma; Sphingolipid; Sphingosine-1-Phosphate; glioma.
Publication types
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Clinical Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / therapeutic use
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Animals
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Brain Neoplasms / drug therapy
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology
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Ceramides / biosynthesis*
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Ceramides / genetics
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Enzyme Inhibitors / therapeutic use
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Follow-Up Studies
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Glioblastoma / drug therapy
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Glioblastoma / genetics
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Glioblastoma / metabolism*
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Glioblastoma / pathology
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Humans
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Lipid Metabolism*
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Lysophospholipids / biosynthesis*
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Lysophospholipids / genetics
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Male
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism*
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Neovascularization, Pathologic / pathology
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Phosphoric Monoester Hydrolases / antagonists & inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Sphingosine / analogs & derivatives*
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Sphingosine / biosynthesis
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Sphingosine / genetics
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Angiogenesis Inhibitors
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Ceramides
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Enzyme Inhibitors
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Lysophospholipids
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Membrane Proteins
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Neoplasm Proteins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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sphingosine 1-phosphate
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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SGPP2 protein, human
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Phosphoric Monoester Hydrolases
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Sphingosine