title: A metabolic shift favoring sphingosine 1-phosphate at the expense of ceramide controls glioblastoma angiogenesis.
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.
authors.affiliation: From the Cure for Life Neuro-oncology Group and.
authors.forename: Hazem J
authors.initials: HJ
authors.lastname: Abuhusain
authors.forename: Azadeh
authors.initials: A
authors.lastname: Matin
authors.forename: Qiao
authors.initials: Q
authors.lastname: Qiao
authors.forename: Han
authors.initials: H
authors.lastname: Shen
authors.forename: Nupur
authors.initials: N
authors.lastname: Kain
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Day
authors.forename: Brett W
authors.initials: BW
authors.lastname: Stringer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Daniels
authors.forename: Maarit A
authors.initials: MA
authors.lastname: Laaksonen
authors.forename: Charlie
authors.initials: C
authors.lastname: Teo
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: McDonald
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Don
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002518:Ceramides / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism; D008246:Lysophospholipids / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D020533:Angiogenesis Inhibitors; D002518:Ceramides; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D042461:Vascular Endothelial Growth Factor A; D000099157:Sphingosine Kinase; C467484:VEGFA protein, human; C060506:sphingosine 1-phosphate; C498526:SGPP2 protein, human
keywords: Angiogenesis; Cancer; Ceramide; Glioblastoma; Sphingolipid; Sphingosine-1-Phosphate; glioma