Sphingolipids are bioactive molecules that have key roles in the regulation of cancer cell signalling to control tumour suppression or survival. Ceramide is a bioeffector molecule that mediates cell death, whereas sphingosine-1-phosphate (S1P) induces tumour cell proliferation, resistance to chemotherapy, radiotherapy or immunotherapy and metastasis.
The metabolic network of sphingolipids provides regulatory nodes for controlling cancer growth and/or proliferation in response to cellular stress, including the activation of enzymes that generate the tumour suppressor ceramide and/or inhibit the conversion of ceramide to S1P or other complex sphingolipids that have pro-survival and/or anti-apoptotic function, such as sphingomyelin and glucosylceramide.
Induction of ceramide generation and/or accumulation mediates cancer cell death via apoptosis, necroptosis or mitophagy, which might be regulated by the distinct functions of de novo-generated endogenous ceramides with different fatty acyl chain lengths. Downstream mechanisms of ceramide in induction of cell death are regulated mainly by its subcellular localization, trafficking and lipid–protein binding between ceramide and target proteins such as phosphatase 2A inhibitor I2PP2A or microtubule-associated protein 1 light chain 3β (LC3B) in cancer cells.
The metabolic conversion of ceramide to S1P increases cancer cell survival via G protein-coupled S1P receptor (S1PR)-dependent or S1PR-independent oncogenic signalling. Systemic S1P mediates host–cancer cell communication to increase tumour metastasis, which involves the function of protein spinster homologue 2 (SPNS2) for S1P secretion from lymphoid endothelial cells and S1PR1-dependent or S1PR2-dependent signalling in cancer cells to induce migration and/or evade immune-cell-mediated cytotoxicity.
There are also receptor-independent roles of endogenous S1P; direct S1P–protein interactions, including with histone deacetylase 1 (HDAC1), HDAC2 and telomerase, regulate cancer cell growth and proliferation.
Targeting sphingolipid metabolism to activate pro-cell death ceramide signalling and/or inhibit pro-survival S1P signalling using genetic, molecular, immunological or pharmacological tools provides novel strategies for the development of new therapies — including immunotherapies — for various cancer types, some of which are under current evaluation in active clinical trials.
Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure–function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P–S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hannun, Y. A. & Obeid, L. M. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 9, 139–150 (2008).
Hannun, Y. A. & Bell, R. M. Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 235, 670–674 (1987).
Dressler, K. A., Mathias, S. & Kolesnick, R. N. Tumor necrosis factor-α activates the sphingomyelin signal transduction pathway in a cell-free system. Science 255, 1715–1718 (1992).
Ogretmen, B. & Hannun, Y. A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 4, 604–616 (2004).
Cuvillier, O. et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381, 800–803 (1996).
Lee, M. J. et al. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279, 1552–1555 (1998).
Pyne, N. J. & Pyne, S. Sphingosine 1-phosphate and cancer. Nat. Rev. Cancer 10, 489–503 (2010).
Morad, S. A. et al. Ceramide-antiestrogen nanoliposomal combinations — novel impact of hormonal therapy in hormone-insensitive breast cancer. Mol. Cancer Ther. 11, 2352–2361 (2012).
Venkataraman, K. et al. Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells. J. Biol. Chem. 277, 35642–35649 (2002). This work provides biochemical details of how CERS proteins function in de novo ceramide synthesis.
Laviad, E. L., Kelly, S., Merrill, A. H. Jr & Futerman, A. H. Modulation of ceramide synthase activity via dimerization. J. Biol. Chem. 287, 21025–21033 (2012).
Pewzner-Jung, Y., Ben-Dor, S. & Futerman, A. H. When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: Insights into the regulation of ceramide synthesis. J. Biol. Chem. 281, 25001–25005 (2006).
Kraveka, J. M. et al. Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J. Biol. Chem. 282, 16718–16728 (2007).
Raichur, S. et al. CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 20, 687–695 (2014).
Jennemann, R. et al. Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum. Mol. Genet. 21, 586–608 (2012).
Ogretmen, B. et al. Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide. J. Biol. Chem. 277, 12960–12969 (2002). This study demonstrates the mechanisms by which exogenous ceramide is utilized for endogenous ceramide generation via the salvage or recycling pathway.
Wijesinghe, D. S., Lamour, N. F., Gomez-Munoz, A. & Chalfant, C. E. Ceramide kinase and ceramide-1-phosphate. Methods Enzymol. 434, 265–292 (2007).
Huitema, K., van den Dikkenberg, J., Brouwers, J. F. & Holthuis, J. C. Identification of a family of animal sphingomyelin synthases. EMBO J. 23, 33–44 (2004).
Watters, R. J. et al. Targeting glucosylceramide synthase synergizes with C6-ceramide nanoliposomes to induce apoptosis in natural killer cell leukemia. Leuk. Lymphoma 54, 1288–1296 (2013).
D'Angelo, G. et al. Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi. Nature 501, 116–120 (2013). This manuscript describes mechanisms of ceramide trafficking by FAPP2 for glucosylceramide generation.
Simanshu, D. K. et al. Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids. Nature 500, 463–467 (2013). This manuscript describes the mechanism of C1P trafficking to regulate inflammation.
Maceyka, M. & Spiegel, S. Sphingolipid metabolites in inflammatory disease. Nature 510, 58–67 (2014).
Huang, W. C. et al. Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans. FASEB J. 30, 2945–2958 (2016).
Zamora-Pineda, J., Kumar, A., Suh, J. H., Zhang, M. & Saba, J. D. Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress. J. Exp. Med. 213, 2773–2791 (2016).
Sandhoff, K. Metabolic and cellular bases of sphingolipidoses. Biochem. Soc. Trans. 41, 562–568 (2013).
Rosenbloom, B. E. et al. Gaucher disease and cancer incidence: a study from the Gaucher Registry. Blood 105, 4569–4572 (2005).
Han, G. et al. Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc. Natl Acad. Sci. USA 106, 8186–8191 (2009).
Bode, H. et al. HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship. Hum. Mol. Genet. 25, 853–865 (2016).
Kramer, R. et al. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. FASEB J. 29, 4461–4472 (2015).
Breslow, D. K. et al. Orm family proteins mediate sphingolipid homeostasis. Nature 463, 1048–1053 (2010).
Siow, D. L. & Wattenberg, B. W. Mammalian ORMDL proteins mediate the feedback response in ceramide biosynthesis. J. Biol. Chem. 287, 40198–40204 (2012).
Meyers-Needham, M. et al. Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells. EMBO Mol. Med. 4, 78–92 (2012).
Koybasi, S. et al. Defects in cell growth regulation by C18:0-ceramide and longevity assurance gene 1 in human head and neck squamous cell carcinomas. J. Biol. Chem. 279, 44311–44319 (2004). This study describes a selective role for CERS1-generated C18 ceramide in head and neck cancer cell death.
Thomas, R. J. et al. HPV/E7 induces chemotherapy-mediated tumor suppression by ceramide-dependent mitophagy. EMBO Mol. Med. 9, 1030–1051 (2017).
Park, W. J. et al. Development of pheochromocytoma in ceramide synthase 2 null mice. Endocr. Relat. Cancer 22, 623–632 (2015).
Fekry, B. et al. CerS6 is a novel transcriptional target of p53 protein activated by non-genotoxic stress. J. Biol. Chem. 291, 16586–16596 (2016).
White-Gilbertson, S. et al. Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells. Oncogene 28, 1132–1141 (2009).
Lee, H. et al. Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS ONE 6, e19783 (2011).
Jensen, S. A. et al. Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. Proc. Natl Acad. Sci. USA 111, 5682–5687 (2014).
Senkal, C. E., Ponnusamy, S., Bielawski, J., Hannun, Y. A. & Ogretmen, B. Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways. FASEB J. 24, 296–308 (2010).
Suzuki, M. et al. Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells. J. Clin. Invest. 126, 254–265 (2016).
Senkal, C. E. et al. Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network. J. Biol. Chem. 286, 42446–42458 (2011).
Schiffmann, S. et al. Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 30, 745–752 (2009).
Rahmaniyan, M. et al. Identification of dihydroceramide desaturase as a direct in vitro target for fenretinide. J. Biol. Chem. 286, 24754–24764 (2011).
Airola, M. V. et al. Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation. Proc. Natl Acad. Sci. USA 114, E5549–E5558 (2017).
Gorelik, A., Illes, K., Heinz, L. X., Superti-Furga, G. & Nagar, B. Crystal structure of mammalian acid sphingomyelinase. Nat. Commun. 7, 12196 (2016).
Santana, P. et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 86, 189–199 (1996).
Carpinteiro, A. et al. Regulation of hematogenous tumor metastasis by acid sphingomyelinase. EMBO Mol. Med. 7, 714–734 (2015).
Shamseddine, A. A. et al. P53-dependent upregulation of neutral sphingomyelinase-2: role in doxorubicin-induced growth arrest. Cell Death Dis. 6, e1947 (2015).
Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008). This manuscript describes the mechanisms underlying ceramide-mediated exosome release.
Chen, Y. et al. Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice. Mol. Cancer Ther. 14, 259–267 (2015).
Barceló- Coblijn, G. et al. Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy. Proc. Natl Acad. Sci. USA 108, 19569–19574 (2011).
Hanada, K. et al. Molecular machinery for non-vesicular trafficking of ceramide. Nature 426, 803–809 (2003). This work provides the details of CERT-dependent ceramide transport from the ER to the Golgi.
Wang, X. et al. Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice. J. Cell Biol. 184, 143–158 (2009).
Heering, J. et al. Loss of the ceramide transfer protein augments EGF receptor signaling in breast cancer. Cancer Res. 72, 2855–2866 (2012).
Lee, A. J. et al. CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction. J. Pathol. 226, 482–494 (2012).
Hullin-Matsuda, F. et al. Limonoid compounds inhibit sphingomyelin biosynthesis by preventing CERT protein-dependent extraction of ceramides from the endoplasmic reticulum. J. Biol. Chem. 287, 24397–24411 (2012).
Wijesinghe, D. S. et al. Ceramide kinase is required for a normal eicosanoid response and the subsequent orderly migration of fibroblasts. J. Lipid Res. 55, 1298–1309 (2014).
Payne, A. W., Pant, D. K., Pan, T. C. & Chodosh, L. A. Ceramide kinase promotes tumor cell survival and mammary tumor recurrence. Cancer Res. 74, 6352–6363 (2014).
Pastukhov, O. et al. The ceramide kinase inhibitor NVP-231 inhibits breast and lung cancer cell proliferation by inducing M phase arrest and subsequent cell death. Br. J. Pharmacol. 171, 5829–5844 (2014).
Kim, J. W. et al. Prognostic value of glucosylceramide synthase and P-glycoprotein expression in oral cavity cancer. Int. J. Clin. Oncol. 21, 883–889 (2016).
Roh, J. L., Kim, E. H., Park, J. Y. & Kim, J. W. Inhibition of glucosylceramide synthase sensitizes head and neck cancer to cisplatin. Mol. Cancer Ther. 14, 1907–1915 (2015).
Stefanovic, M. et al. Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma. Oncotarget 7, 8253–8267 (2016).
Liu, Y. Y. et al. Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells. Cancer Res. 71, 2276–2285 (2011).
Gupta, V. et al. Ceramide glycosylation by glucosylceramide synthase selectively maintains the properties of breast cancer stem cells. J. Biol. Chem. 287, 37195–37205 (2012).
Eliyahu, E., Park, J. H., Shtraizent, N., He, X. & Schuchman, E. H. Acid ceramidase is a novel factor required for early embryo survival. FASEB J. 21, 1403–1409 (2007).
Cheng, J. C. et al. Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse. J. Clin. Invest. 123, 4344–4358 (2013).
Beckham, T. H. et al. Acid ceramidase induces sphingosine kinase 1/S1P receptor 2-mediated activation of oncogenic Akt signaling. Oncogenesis 2, e49 (2013).
Tirodkar, T. S. et al. Expression of ceramide synthase 6 transcriptionally activates acid ceramidase in a c-Jun N-terminal kinase (JNK)-dependent manner. J. Biol. Chem. 290, 13157–13167 (2015).
Airola, M. V. et al. Structural basis for ceramide recognition and hydrolysis by human neutral ceramidase. Structure 23, 1482–1491 (2015).
Garcia-Barros, M. et al. Role of neutral ceramidase in colon cancer. FASEB J. 30, 4159–4171 (2016).
Liakath-Ali, K. et al. Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure. J. Pathol. 239, 374–383 (2016).
Mao, Z. et al. Alkaline ceramidase 2 (ACER2) and its product dihydrosphingosine mediate the cytotoxicity of N-(4-hydroxyphenyl)retinamide in tumor cells. J. Biol. Chem. 285, 29078–29090 (2010).
Wang, K. et al. Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system. Cell Death Dis. 7, e2124 (2016).
Xiong, Y., Yang, P., Proia, R. L. & Hla, T. Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development. J. Clin. Invest. 124, 4823–4828 (2014).
Wang, Z. et al. Molecular basis of sphingosine kinase 1 substrate recognition and catalysis. Structure 21, 798–809 (2013).
Kawamori, T. et al. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 23, 405–414 (2009).
Zhang, Y. et al. Sphingosine kinase 1 and cancer: a systematic review and meta-analysis. PLoS ONE. 9, e90362 (2014).
Postepska-Igielska, A. et al. LncRNA Khps1 regulates expression of the proto-oncogene SPHK1 via triplex-mediated changes in chromatin structure. Mol. Cell 60, 626–636 (2015).
Wang, Q. et al. Prognostic significance of sphingosine kinase 2 expression in non-small cell lung cancer. Tumour Biol. 35, 363–368 (2014).
Zhang, L., Liu, X., Zuo, Z., Hao, C. & Ma, Y. Sphingosine kinase 2 promotes colorectal cancer cell proliferation and invasion by enhancing MYC expression. Tumour Biol. 37, 8455–8460 (2016).
Hait, N. C., Bellamy, A., Milstien, S., Kordula, T. & Spiegel, S. Sphingosine kinase type 2 activation by ERK-mediated phosphorylation. J. Biol. Chem. 282, 12058–12065 (2007).
Degagne, E. et al. Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. J. Clin. Invest. 124, 5368–5384 (2014).
Oskouian, B. et al. Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Proc. Natl Acad. Sci. USA 103, 17384–17389 (2006).
Gao, X. Y. et al. Inhibition of sphingosine-1-phosphate phosphatase 1 promotes cancer cells migration in gastric cancer: clinical implications. Oncol. Rep. 34, 1977–1987 (2015).
Obeid, L. M., Linardic, C. M., Karolak, L. A. & Hannun, Y. A. Programmed cell death induced by ceramide. Science 259, 1769–1771 (1993). This is a key manuscript demonstrating that ceramide induces apoptosis.
Siskind, L. J. et al. Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels. J. Biol. Chem. 283, 6622–6630 (2008).
Chang, K. T. et al. Ceramide channels: destabilization by Bcl-xL and role in apoptosis. Biochim. Biophys. Acta 1848, 2374–2384 (2015).
Chipuk, J. E. et al. Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell 148, 988–1000 (2012). This manuscript provides mechanisms for BAX and BAK regulation by sphingolipid metabolism.
Blom, T. et al. LAPTM4B facilitates late endosomal ceramide export to control cell death pathways. Nat. Chem. Biol. 11, 799–806 (2015).
Mukhopadhyay, A. et al. Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling. FASEB J. 23, 751–763 (2009).
Saddoughi, S. A. et al. Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol. Med. 5, 105–121 (2013). This study shows that ceramide binds I2PP2A to activate PP2A-dependent necroptosis.
Saddoughi, S. A. & Ogretmen, B. Diverse functions of ceramide in cancer cell death and proliferation. Adv. Cancer Res. 117, 37–58 (2013).
Jiang, W. & Ogretmen, B. Autophagy paradox and ceramide. Biochim. Biophys. Acta 1841, 783–792 (2014).
Hernandez-Tiedra, S. et al. Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy 12, 2213–2229 (2016).
Corcelle-Termeau, E. et al. Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure. Autophagy 12, 833–849 (2016).
Sentelle, R. D. et al. Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat. Chem. Biol. 8, 831–838 (2012). This manuscript shows that ceramide directly binds LC3B-II to recruit autophagosomes to mitochondria for mitophagy induction.
Dany, M. et al. Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML. Blood 128, 1944–1958 (2016).
Salazar, M. et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J. Clin. Invest. 119, 1359–1372 (2009).
Lepine, S., Allegood, J. C., Edmonds, Y., Milstien, S. & Spiegel, S. Autophagy induced by deficiency of sphingosine-1-phosphate phosphohydrolase 1 is switched to apoptosis by calpain-mediated autophagy-related gene 5 (Atg5) cleavage. J. Biol. Chem. 286, 44380–44390 (2011).
Fekry, B., Esmaeilniakooshkghazi, A., Krupenko, S. A. & Krupenko, N. I. Ceramide synthase 6 is a novel target of methotrexate mediating its antiproliferative effect in a p53-dependent manner. PLoS ONE 11, e0146618 (2016).
Heffernan-Stroud, L. A. et al. Defining a role for sphingosine kinase 1 in p53-dependent tumors. Oncogene 31, 1166–1175 (2012).
Kitatani, K. et al. Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene 35, 2801–2812 (2016).
Pitson, S. M. et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J. 22, 5491–5500 (2003).
Takabe, K. et al. Estradiol induces export of sphingosine 1-phosphate from breast cancer cells via ABCC1 and ABCG2. J. Biol. Chem. 285, 10477–10486 (2010).
Hisano, Y., Kobayashi, N., Yamaguchi, A. & Nishi, T. Mouse SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial cells. PLoS ONE 7, e38941 (2012).
van der Weyden, L. et al. Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature 541, 233–236 (2017). This manuscript describes a mechanism for S1P secretion via SPNS2 from lymphoid endothelial cells to regulate metastasis.
Ponnusamy, S. et al. Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1-phosphate signalling to regulate tumour metastasis. EMBO Mol. Med. 4, 761–775 (2012). This manuscript describes a role for systemic S1P in inducing tumour metastasis by providing communication between host and cancer cells via S1PR2 signalling.
Visentin, B. et al. Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9, 225–238 (2006). This manuscript provides validation of an anti-S1P antibody that neutralizes S1P signalling to promote tumour suppression.
Liang, J. et al. Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell 23, 107–120 (2013). This manuscript describes a role for systemic S1P in inducing STAT3-dependent inflammation and colitis-associated colon cancer.
Brizuela, L. et al. Osteoblast-derived sphingosine 1-phosphate to induce proliferation and confer resistance to therapeutics to bone metastasis-derived prostate cancer cells. Mol. Oncol. 8, 1181–1195 (2014).
Liu, Y. et al. S1PR1 is an effective target to block STAT3 signaling in activated B cell-like diffuse large B-cell lymphoma. Blood 120, 1458–1465 (2012).
Feng, H. et al. T-Lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation. Cancer Cell 18, 353–366 (2010).
Powell, J. A. et al. Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. Blood 129, 771–782 (2017).
Adada, M. M. et al. Intracellular sphingosine kinase 2-derived sphingosine-1-phosphate mediates epidermal growth factor-induced ezrin-radixin-moesin phosphorylation and cancer cell invasion. FASEB J. 29, 4654–4669 (2015).
Du, W. et al. S1P2, the G protein-coupled receptor for sphingosine-1-phosphate, negatively regulates tumor angiogenesis and tumor growth in vivo in mice. Cancer Res. 70, 772–781 (2010).
Hirata, N. et al. Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation. Nat. Commun. 5, 4806 (2014).
Zhao, J. et al. TGF-β/SMAD3 pathway stimulates sphingosine-1 phosphate receptor 3 expression: implication of sphingosine-1 phosphate receptor 3 in lung adenocarcinoma progression. J. Biol. Chem. 291, 27343–27353 (2016).
Ohotski, J. et al. Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor-negative breast cancer. Br. J. Cancer 106, 1453–1459 (2012).
Ohotski, J., Rosen, H., Bittman, R., Pyne, S. & Pyne, N. J. Sphingosine kinase 2 prevents the nuclear translocation of sphingosine 1-phosphate receptor-2 and tyrosine 416 phosphorylated c-Src and increases estrogen receptor negative MDA-MB-231 breast cancer cell growth: the role of sphingosine 1-phosphate receptor-4. Cell Signal. 26, 1040–1047 (2014).
Andrieu, G. et al. Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression. Sci Signal. 10, eaah4007 (2017).
Alvarez, S. E. et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465, 1084–1088 (2010). This manuscript describes SPHK1-generated S1P signalling in TRAF2 binding and NF- κ B activation.
Xiong, Y. et al. Sphingosine kinases are not required for inflammatory responses in macrophages. J. Biol. Chem. 288, 32563–32573 (2013).
Etemadi, N. et al. TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. Elife 4, e10592 (2015).
Parham, K. A. et al. Sphingosine 1-phosphate is a ligand for peroxisome proliferator-activated receptor-γ that regulates neoangiogenesis. FASEB J. 29, 3638–3653 (2015).
Hait, N. C. et al. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325, 1254–1257 (2009). This work describes a role for SPHK2-generated S1P in binding HDAC1 and HDAC2 and inhibiting histone deacetylation.
Strub, G. M. et al. Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. FASEB J. 25, 600–612 (2011).
Panneer Selvam, S. et al. Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation. Sci. Signal. 8, ra58 (2015). This manuscript describes a mechanism for SPHK2-generated S1P to directly bind TERT to stabilize telomerase and prevent telomere damage via the phosphomimic function of S1P.
Bose, R. et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82, 405–414 (1995).
Saddoughi, S. A. et al. Results of a phase II trial of gemcitabine plus doxorubicin in patients with recurrent head and neck cancers: serum C18-ceramide as a novel biomarker for monitoring response. Clin. Cancer Res. 17, 6097–6105 (2011).
Senkal, C. E. et al. Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas. Mol. Cancer Ther. 6, 712–722 (2007).
Deng, X. et al. Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans. Science 322, 110–115 (2008). This work describes mechanistic details of how ceramide mediates cell death in response to radiation.
Rotolo, J. et al. Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice. J. Clin. Invest. 122, 1786–1790 (2012).
Liu, Y. Y. et al. A role for ceramide in driving cancer cell resistance to doxorubicin. FASEB J. 22, 2541–2551 (2008).
Zhang, X. et al. Doxorubicin influences the expression of glucosylceramide synthase in invasive ductal breast cancer. PLoS ONE 7, e48492 (2012).
Rosa, R. et al. Sphingosine kinase 1 overexpression contributes to cetuximab resistance in human colorectal cancer models. Clin. Cancer Res. 19, 138–147 (2013).
Salas, A. et al. Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A. Blood 117, 5941–5952 (2011).
Huang, X. et al. miRNA-95 mediates radioresistance in tumors by targeting the sphingolipid phosphatase SGPP1. Cancer Res. 73, 6972–6986 (2013).
Fang, V. et al. Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-γ response. Nat. Immunol. 18, 15–25 (2017).
Liu, F. et al. Ceramide activates lysosomal cathepsin B and cathepsin D to attenuate autophagy and induces ER stress to suppress myeloid-derived suppressor cells. Oncotarget 7, 83907–83925 (2016).
Nair, S. et al. Clonal immunoglobulin against lysolipids in the origin of myeloma. N. Engl. J. Med. 374, 555–561 (2016).
Pandey, M. K. et al. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease. Nature 543, 108–112 (2017).
Sofi, M. H. et al. Ceramide synthesis regulates T cell activity and GVHD development. JCI Insight 2, e91701 (2017).
Le Nours, J. et al. Atypical natural killer T-cell receptor recognition of CD1d-lipid antigens. Nat. Commun. 7, 10570 (2016).
Lee, H. et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat. Med. 16, 1421–1428 (2010).
Deng, Z. et al. Enterobacteria-secreted particles induce production of exosome-like S1P-containing particles by intestinal epithelium to drive Th17-mediated tumorigenesis. Nat. Commun. 6, 6956 (2015).
Garris, C. S. et al. Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat. Immunol. 14, 1166–1172 (2013).
Luo, B. et al. Erythropoeitin signaling in macrophages promotes dying cell clearance and immune tolerance. Immunity 44, 287–302 (2016).
Cohen, J. A. et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362, 402–415 (2010).
Kappos, L. et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362, 387–401 (2010).
Neviani, P. et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J. Clin. Invest. 123, 4144–4157 (2013).
Beljanski, V., Lewis, C. S. & Smith, C. D. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol. Ther. 11, 524–534 (2011).
Senkal, C. E. et al. Potent antitumor activity of a novel cationic pyridinium-ceramide alone or in combination with gemcitabine against human head and neck squamous cell carcinomas in vitro and in vivo. J. Pharmacol. Exp. Ther. 317, 1188–1199 (2006).
Beckham, T. H. et al. LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria. J. Pharmacol. Exp. Ther. 344, 167–178 (2013).
Liu, X. et al. Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia. Blood 116, 4192–4201 (2010).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02834611 (2016).
Kapitonov, D. et al. Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res. 69, 6915–6923 (2009).
Schnute, M. E. et al. Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1. Biochem. J. 444, 79–88 (2012).
Wang, J., Knapp, S., Pyne, N. J., Pyne, S. & Elkins, J. M. Crystal structure of sphingosine kinase 1 with PF-543. ACS Med. Chem. Lett. 5, 1329–1333 (2014).
Ju, T., Gao, D. & Fang, Z. Y. Targeting colorectal cancer cells by a novel sphingosine kinase 1 inhibitor PF-543. Biochem. Biophys. Res. Commun. 470, 728–734 (2016).
Kennedy, P. C. et al. Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J. Pharmacol. Exp. Ther. 338, 879–889 (2011).
Li, M. H. et al. Antitumor activity of a novel sphingosine-1-phosphate 2 antagonist, AB1, in neuroblastoma. J. Pharmacol. Exp. Ther. 354, 261–268 (2015).
Pal, S. K. et al. A phase 2 study of the sphingosine-1-phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma. Cancer 123, 576–582 (2017).
Lewis, C. S., Voelkel-Johnson, C. & Smith, C. D. Suppression of c-Myc and RRM2 expression in pancreatic cancer cells by the sphingosine kinase-2 inhibitor ABC294640. Oncotarget 7, 60181–60192 (2016).
Venant, H. et al. The sphingosine kinase 2 inhibitor ABC294640 reduces the growth of prostate cancer cells and results in accumulation of dihydroceramides in vitro and in vivo. Mol. Cancer Ther. 14, 2744–2752 (2015).
Britten, C. D. et al. A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 23, 4642–4650 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02939807 (2016).
Venkata, J. K. et al. Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood 124, 1915–1925 (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02757326 (2016).
Qin, Z. et al. Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma. Mol. Cancer Ther. 13, 154–164 (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02229981 (2014).
Bielawski, J. et al. Comprehensive quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Methods Mol. Biol. 579, 443–467 (2009).
Shaner, R. L. et al. Quantitative analysis of sphingolipids for lipidomics using triple quadrupole and quadrupole linear ion trap mass spectrometers. J. Lipid Res. 50, 1692–1707 (2009).
Senkal, C. E. et al. Ceramide is metabolized to acylceramide and stored in lipid droplets. Cell Metab. 25, 686–697 (2017).
Russo, S. B., Tidhar, R., Futerman, A. H. & Cowart, L. A. Myristate-derived d16:0 sphingolipids constitute a cardiac sphingolipid pool with distinct synthetic routes and functional properties. J. Biol. Chem. 288, 13397–13409 (2013).
Menuz, V. et al. Protection of C. elegans from anoxia by HYL-2 ceramide synthase. Science 324, 381–384 (2009).
Mesicek, J. et al. Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells. Cell Signal 22, 1300–1307 (2010).
The author thanks N. Oleinik and C. Frichtel for their editorial assistance. The author is also thankful to Z. Szulc for his assistance with the chemical structures of sphingolipid molecules and the members of his laboratory for their helpful discussions. The author apologizes to those investigators whose publications were not mentioned in this Review owing to space limitations. This work is supported by research grants from the NIH (R01-DE16572, R01-CA88932, R01-CA173687 and P01-CA203628), and the South Carolina SmartState Endowment for Lipidomics and Drug Discovery.
The author declares no competing financial interests.
A type of ceramide (globoside) that is incorporated with lactose.
A subtype of glycolipids that contain amino alcohol sphingosine, which include cerebrosides, gangliosides and globosides.
- Lysosomal storage diseases
A group of inherited metabolic disorders that result from defective lysosomal function and are mainly associated with accumulation of sphingolipids and/or glycosphingolipids.
A rare tumour of the adrenal gland.
A class of bioactive lipid derived from polyunsaturated fatty acids, which include prostaglandins, leukotrienes and thromboxanes.
Ceramide molecules that contain a hexosyl group, such as monohexosylceramide (glucosylceramide).
A programmed necrosis involving receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 signalling that ruptures the plasma membrane, leading to cellular rupture and death.
- Mitochondrial outer membrane permeabilization
(MOMP). A key step in the execution of apoptosis, regulated by BCL-2 family member proteins, that leads to the release of pro-cell death factors, such as cytochrome c, from the internal mitochondrial membrane to engage with caspase signalling.
A form of autophagy that selectively degrades damaged mitochondria through the actions of double-membraned autophagosomes.
- Survival autophagy
A type of macroautophagy that mediates a vacuolar and self-digesting mechanism responsible for the removal of damaged proteins and/or organelles by double-membraned autophagosomes associated with lysosomes, providing nutrients for cell survival during stress conditions such as starvation.
- Mitochondrial fission
The partition of the mitochondrial membrane between two forming daughter mitochondria, which is regulated by a set of proteins including dynamin-related protein 1 (DRP1), parkin and PTEN-induced putative kinase 1 (PINK1).
A condition defined by the presence of abnormally low levels of lymphocytes (white blood cells or immune cells) in the blood.
- Gastrointestinal radiation syndrome
A syndrome caused by exposure to high doses of radiation that induces substantial cell death in the gastrointestinal tract.
- Allogeneic haematopoietic stem cell transplantation
(Allo-HSCT). A transplantation of multipotent haematopoietic stem cells derived from bone marrow, peripheral blood or umbilical cord blood from a genetically dissimilar donor for the treatment of patients with multiple myeloma or leukaemia.
- Graft-versus-host disease
A medical complication that might occur after allogeneic haematopoietic stem cell transplantation, in which transplanted immune cells from a donor (graft) recognize the recipient (host) tissues as foreign (non-self), attacking the host cells and resulting in tissue or organ damage.
About this article
Cite this article
Ogretmen, B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 18, 33–50 (2018). https://doi.org/10.1038/nrc.2017.96
Medial calcification in the arterial wall of smooth muscle cell‐specific Smpd1 transgenic mice: A ceramide‐mediated vasculopathy
Journal of Cellular and Molecular Medicine (2020)
Establishment of a Measurement System for Sphingolipids in the Cerebrospinal Fluid Based on Liquid Chromatography-Tandem Mass Spectrometry, and Its Application in the Diagnosis of Carcinomatous Meningitis
The Journal of Applied Laboratory Medicine (2020)
Drug Resistance Updates (2020)
A simple method for sphingolipid analysis of tissues embedded in optimal cutting temperature compound
Journal of Lipid Research (2020)
The Journal of Allergy and Clinical Immunology: In Practice (2020)