A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis*
| Autor: | Azadeh Matin, Bryan W. Day, Anthony S. Don, Hazem J. Abuhusain, Nupur Kain, Brett W. Stringer, Maarit A. Laaksonen, Qiao Qiao, Benjamin Daniels, Han Shen, Kerrie L. McDonald, Charlie Teo |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A medicine.medical_specialty Ceramide Angiogenesis Angiogenesis Inhibitors Ceramides Biochemistry chemistry.chemical_compound Mice Sphingosine Internal medicine Glioma medicine Animals Humans Sphingosine-1-phosphate Enzyme Inhibitors Molecular Biology biology Neovascularization Pathologic Brain Neoplasms organic chemicals Membrane Proteins Cell Biology Lipid signaling medicine.disease Lipid Metabolism Sphingolipid Lipids Phosphoric Monoester Hydrolases Neoplasm Proteins carbohydrates (lipids) Phosphotransferases (Alcohol Group Acceptor) Endocrinology chemistry Sphingosine kinase 1 Cancer research biology.protein lipids (amino acids peptides and proteins) Lysophospholipids Glioblastoma Follow-Up Studies |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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