Abstract
The sphingolipids are one of the major lipid families in eukaryotes, incorporating a diverse array of structural variants that exert a powerful influence over cell fate and physiology. Increased expression of sphingosine kinase 1 (SPHK1), which catalyses the synthesis of the pro-survival, pro-angiogenic metabolite sphingosine 1-phosphate (S1P), is well established as a hallmark of multiple cancers. Metabolic alterations that reduce levels of the pro-apoptotic lipid ceramide, particularly its glucosylation by glucosylceramide synthase (GCS), have frequently been associated with cancer drug resistance. However, the simple notion that the balance between ceramide and S1P, often referred to as the sphingolipid rheostat, dictates cell survival contrasts with recent studies showing that highly potent and selective SPHK1 inhibitors do not affect cancer cell proliferation or survival, and studies demonstrating higher ceramide levels in some metastatic cancers. Recent reports have implicated other sphingolipid metabolic enzymes such as acid sphingomyelinase (ASM) more strongly in cancer pathogenesis, and highlight lysosomal sphingolipid metabolism as a possible weak point for therapeutic targeting in cancer. This review describes the evidence implicating different sphingolipid metabolic enzymes and their products in cancer pathogenesis, and suggests how newer systems-level approaches may improve our overall understanding of how oncogenic transformation reconfigures sphingolipid metabolism.
Highlights
Metabolic state changes, such as heightened glycolysis and lipid biosynthesis, are a hallmark of many, if not all, cancers [1,2]
For comprehensive reviews on pharmacology related to inhibition of sphingosine kinases, ceramidases, sphingomyelinases, and glucosylceramide synthase, the reader is referred to recent reviews [3,4,5,6]
sphingosine 1-phosphate (S1P) is derived in two enzymatic steps from the central sphingolipid metabolite, ceramide, which is generally regarded as having tumour suppressive signalling properties [10,11]
Summary
Metabolic state changes, such as heightened glycolysis and lipid biosynthesis, are a hallmark of many, if not all, cancers [1,2]. Sphingolipids tend to associate more tightly with each other in cell membranes than phospholipids, thereby modulating the fluidity of membranes and forming the basis, together with cholesterol, for the densely packed regions of the membrane referred to as lipid rafts [7,8] In addition to this fundamental membrane role, glycosphingolipids pattern the surface of the cell with a diverse array of oligosaccharide structures that dictate cell-cell interactions as well as modulating intracellular signalling. S1P is derived in two enzymatic steps from the central sphingolipid metabolite, ceramide, which is generally regarded as having tumour suppressive signalling properties [10,11] The balance between these two metabolites has been termed the “sphingolipid rheostat” [12] and has attracted a great deal of attention in regard to its control over cancer cell survival. ASA: Arylsulfatase A; ASAH1: Acid ceramidase; ASM: Acid sphingomyelinase; Cer1P: Ceramide 1-phosphate; CERK: Ceramide kinase; CERS: Ceramide synthase; CERT: Ceramide transfer protein; CGT: Ceramide galactosyltransferase; CST: Cerebroside sulfotransferase; DEGS1/2: Dihydroceramide desaturase 1 or 2; GCS: Glucosylceramide synthase; KDS: 3-ketosphinganine reductase; LacCer synthase: Lactosylceramide synthase; NSM: Neutral sphingomyelinase; S1P: Sphingosine 1-phosphate; SGPL: S1P lyase; SGPP1/2: Sphingosine 1-phosphate phosphatase 1 or 2; SM: Sphingomyelin; SPHK1/2 : Sphingosine kinases 1 or 2; SPT: Serine palmitoyltransferase
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