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

• Published in: The Journal of biological chemistry Vol. 288; no. 52; pp. 37355 - 37364
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.12.2013; American Society for Biochemistry and Molecular Biology
• 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; Angiogenesis; Sphingosine-1-Phosphate; Glioblastoma; Ceramide; Sphingolipid; glioma; Cancer
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.494740

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.