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.
Highlights
The sphingolipid metabolite sphingosine 1-phosphate (S1P) is a potent angiogenic factor
Increased S1P content in the tumors was significantly correlated with increased sphingosine kinase 1 (SPHK1) and decreased sphingosine phosphate phosphatase 2 (SGPP2) expression
Gliomas Are Characterized by Decreased Ceramide and Increased S1P—The levels of six related groups of sphingolipids, shown in Fig. 1A, comprising 90 individual metabolites, were quantified in normal gray matter (NGM), AII, AIII, and GBM tissue samples
Summary
The sphingolipid metabolite sphingosine 1-phosphate (S1P) is a potent angiogenic factor. Ceramide itself plays an important role in the execution of cell death induced by radiotherapy, chemotherapeutics, lethal autophagy, or proapoptotic TNF family ligands (6 – 8) These prodeath functions of ceramide are mediated through direct binding to protein targets such as the tumor suppressor phosphatase PP2A [9], kinase suppressor of Ras [10], and autophagy protein LC3B-II [7]. The capacity for rapid enzymatic interconversion of ceramide and S1P has given rise to the “sphingolipid rheostat” hypothesis, whereby the balance between prodifferentiative, proapoptotic ceramide and proproliferative, prosurvival S1P exerts a powerful influence over cancer cell fate This is supported by a large body of data demonstrating an important role for SPHK1 in cellular transformation and cancer progression. A highly specific SPHK1 inhibitor, not affecting GBM cell proliferation, potently inhibits the transfer of angiogenic signals from GBM cells to cocultured endothelial cells
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