Table 1.
Sphingolipid species and their key cellular functions
| Cellular process | Sphingolipid species (and enzymes) involved |
|---|---|
| Ceramide | |
| Cell death | • ↑C18 ceramide in chemotherapy-induced cell death in human HNSCCs • ↑C16 ceramide via CerS activation induced by a variety of cell stressors • Exogenous C16 ceramide • ↑C16 and C24 ceramide in neutrophils • ↓C16 ceramide via CerS6 downregulation in human HNSCCs • ↑C16 ceramide induced by ACDase inhibition • aSMase-dependent C16 ceramide generation |
| Cell differentiation | • ↑Total ceramides |
| Stimulation of cell migration and/or invasion in cancer cells | • ↓C16 ceramide via downregulation of CERS6 during epithelial-to-mesenchymal transition • ↑Ceramides in arsenic trioxide in HCCLM3 hepatocarcinoma cells |
| Cell proliferation | • ↑C24 and C24:1 ceramide via overexpression of CerS2 |
| Cell cycle arrest | • Exogenous C2 or C6 ceramide |
| Senescence | • ↑Total ceramides • Exogenous C8 ceramide |
| Necrosis | • ↑Total ceramides • Exogenous C2 or C6 ceramide |
| Necroptosis | • Exogenous C16 ceramide • ↑C16 ceramide in TNFα-treated cells |
| Autophagy | • ↑Ceramide due to cell stressor • Exogenous C2 or C6 ceramide in tamoxifen-treated cells • ↑C16 ceramide |
| Mitophagy | • ↑C18 ceramide via CerS1 activity |
| Cytoskeleton rearrangement | • ↑Total ceramides via activation of aSMase or exogenous bSMase |
| Insulin resistance and cellular metabolism | • ↑Total ceramides in high-fat diet administration and/or palmitate treatment via CerS, nSMase or aSMase activity • ↑C16 ceramide due to CerS6 upregulation upon high-fat diet administration • Exogenous C2 or C6 ceramides |
| S1P | |
| Cell survival | • ↑S1P |
| Autophagy | • Exogenous S1P • ↑S1P via overexpression of SK1 during cell starvation |
| Inflammation | • ↑S1P in TNFα-treated cells • ↑S1P in S1P lyase-deficient mice • ↑S1P via upregulation of SK1 |
| Cell migration and invasion | • ↑S1P via SK2 activation during EGF stimulation • ↑S1P via overexpression of SK2 or ACER2 • ↑S1P via SK1 mRNA and/or protein expression in cancer cells • Exogenous S1P |
| Cytoskeleton rearrangement | • ↑S1P in HeLa cells treated with bSMase or NCDase • ↑S1P in EGF-treated cells • Exogenous S1P • ↑Total ceramide via activation of aSMase in cisplatin-treated cells |
| Sphingosine | |
| Apoptosis | • ↑Sphingosine in cancer cells induced by environmental stress, chemotherapeutic treatment and apoptotic stimulus • Exogenous sphingosine treatment • ↑Sphingosine via SK inhibition |
| Cell cycle arrest | • ↑Sphingosine during DNA damage • ↑Sphingosine via upregulation of ACER2 • Exogenous sphingosine |
| Cell differentiation | • ↑Sphingosine via upregulation of ACER1 and ACDase in human epidermal keratinocytes • Exogenous sphingosine |
| C1P | |
| Cell migration | • ↑C1P by upregulation of CERK • Exogenous C1P treatment |
| Cell proliferation | • Exogenous C1P • ↑C1P in cells overexpressing CERK • ↑C1P production in cells cultured in medium supplemented with fetal bovine serum |
| Inhibition of apoptosis | • Exogenous C1P |
| Regulation of inflammation | • Exogenous C1P • ↑C1P via CERK upregulation upon IL-1β or TNFα treatment or stimulation of resting macrophages with macrophage colony-stimulating factor |
| Dihydroceramide | |
| Cell cycle arrest | • ↑Total dihydroceramides via downregulation of DEGS1 |
| Apoptosis | • ↑C16 dihydroceramide • ↑C16 dihydroceramide in 4-HPR-treated cells • ↑C22 and C24 dihydroceramide in T cell acute lymphoblastic leukaemia cell lines |
| Inhibition of cell growth | • ↑C16 dihydroceramide induced by the SK2 inhibitor ABC294640 in TRAMP-C2 cells • ↑Total dihydroceramides via downregulation of DEGS1 or DEGS2 or direct treatment with dihydroceramides |
| Autophagy | • ↑Total dihydroceramides • ↑C16 dihydroceramide in resveratrol-treated HGC-27 human gastric cancer cells |
| Sphingomyelin | |
| Cell growth | • ↑Sphingomyelin via SMS1 overexpression • Exogenous sphingomyelin • ↑Sphingomyelin via basic fibroblast growth factor-dependent stimulation of SMS |
| Cell adhesion | • ↑Sphingomyelin in cells treated with phorbol ester stimulated cell adhesion • ↓Sphingomyelin induced by nSMase treatment caused detachment |
| Galactosylceramide | |
| Inflammation | • ↑Galactosylceramides in GALC mutant mice • Exogenous galactosylceramide treatment stimulates natural killer T cells |
| HIV-1 infection | • Binding of HIV-1 gp120 to GalCer • HIV-1 infection in CD4–GalCer+ T lymphocytes |
| Glucosylceramide | |
| Multidrug resistance in cancer cells | • ↑Glucosylceramides via GCS overexpression in multiple multidrug-resistant tumours and cancer cell lines |
| Inflammation | • ↑Glucosylceramides induced by mutations in the β-glucosylceramidase beta gene (Gaucher disease) |
| Cell adhesion | • ↑Glucosylceramides via GCS overexpression • ↑Glucosylceramides in cells treated with 12-O-tetradecanoylphorbol-13-acetate |
| Cell differentiation | • ↑Glucosylceramides in cells treated with 12-O-tetradecanoylphorbol-13-acetate |
| Lactosylceramide | |
| Cell proliferation | • ↑Lactosylceramides due to upregulation of LCS activity |
| Cell adhesion | • ↑Lactosylceramides due to upregulation of LCS activity • Exogenous lactosylceramide treatment |
| Angiogenesis | • ↑Lactosylceramides upon vascular endothelial growth factor treatment • Exogenous lactosylceramide |
| Reactive oxygen species generation | • Exogenous lactosylceramide |
| Inflammation | • Exogenous lactosylceramide • ↑Lactosylceramides via upregulation of LCS activity in cells treated with lipopolysaccharide and interferon-γ • ↑Lactosylceramides induced by cigarette smoke |
For references see full version of the table in Supplementary information S2 (table). The full version also contains structures of the sphingolipid species. 4-HPR, fenretinide; ACDase, acid ceramidase; ACER, alkaline ceramidase; aSMase, acid sphingomyelinase; bSMase, bacterial sphingomyelinase; C1P, ceramide-1-phosphate; CERK, ceramide kinase; CerS, ceramide synthase; DEGS1, sphingolipid δ (4)-desaturase DES1; EGF, epidermal growth factor; GALC, galactosylceramidase; GalCer, galactosylceramide; GCS, glucosylceramide synthase; HNSCC, head and neck squamous cell carcinoma; IL-1β, interleukin-1β; LCS, lactosylceramide synthase; NCDase, neutral ceramidase; nSMase, neutral sphingomyelinase; S1P, sphingosine-1-phosphate; SK1, sphingosine kinase 1; SK2, sphingosine kinase 2; SMS, sphingomyelin synthase; TNFα, tumour necrosis factor α.