Sphingolipid metabolism in cancer signalling and therapy

Nature Reviews Cancer

Volumn 18, Issue 1, 2017, Pages 33-50

  Ogretmen, Besim ^a,b  

^a MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

^b MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (4 CHLOROPHENYL) N (4 PYRIDINYLMETHYL)ADAMANTANE 1 CARBOXAMIDE; ACID CERAMIDASE; ALKALINE CERAMIDASE 1; ALKALINE CERAMIDASE 2; ALKALINE CERAMIDASE 3; CERAMIDE; CERAMIDE KINASE; CERAMIDE SYNTHASE 1; CERAMIDE SYNTHASE 2; CERAMIDE SYNTHASE 3; CERAMIDE SYNTHASE 4; CERAMIDE SYNTHASE 5; CERAMIDE SYNTHASE 6; CERAMIDE TRANSFER PROTEIN; DIHYDROCERAMIDE DESATURASE; FINGOLIMOD; GLUCOSYLCERAMIDE; NEUTRAL CERAMIDASE; SONEPCIZUMAB; SPHINGOLIPID; SPHINGOMYELIN PHOSPHODIESTERASE; SPHINGOMYELIN SYNTHASE 1; SPHINGOSINE 1 PHOSPHATE; SPHINGOSINE 1 PHOSPHATE RECEPTOR; SPHINGOSINE KINASE 1; SPHINGOSINE KINASE 2; UNCLASSIFIED DRUG; LYSOPHOSPHOLIPID; SPHINGOSINE; SPHINGOSINE 1-PHOSPHATE;

APOPTOSIS; AUTOPHAGY; CANCER CHEMOTHERAPY; CANCER GROWTH; CANCER IMMUNOTHERAPY; CANCER RADIOTHERAPY; CANCER RESISTANCE; CANCER THERAPY; CELL CYCLE ARREST; CELL PROLIFERATION; CELL STRESS; ENDOPLASMIC RETICULUM STRESS; HUMAN; LIPOGENESIS; METASTASIS; MITOPHAGY; MULTICENTER STUDY (TOPIC); NECROPTOSIS; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SPHINGOLIPID METABOLISM; TUMOR IMMUNOLOGY; ANALOGS AND DERIVATIVES; ANIMAL; DRUG RESISTANCE; METABOLISM; NEOPLASM; PATHOLOGY; PHYSIOLOGY;

ANIMALS; APOPTOSIS; CERAMIDES; DRUG RESISTANCE, NEOPLASM; HUMANS; LYSOPHOSPHOLIPIDS; NEOPLASMS; SIGNAL TRANSDUCTION; SPHINGOLIPIDS; SPHINGOSINE;

EID: 85038830855     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc.2017.96     Document Type: Review

References (176)

1. Hannun, Y. A. and Obeid, L. M. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 9, 139-150 (2008).
2. Hannun, Y. A. and Bell, R. M. Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 235, 670-674 (1987).
3. Dressler, K. A., Mathias, S. and Kolesnick, R. N. Tumor necrosis factor-α activates the sphingomyelin signal transduction pathway in a cell-free system. Science 255, 1715-1718 (1992).
4. Ogretmen, B. and Hannun, Y. A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 4, 604-616 (2004).
5. Cuvillier, O. et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381, 800-803 (1996).
6. Lee, M. J. et al. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279, 1552-1555 (1998).
7. Pyne, N. J. and Pyne, S. Sphingosine 1-phosphate and cancer. Nat. Rev. Cancer 10, 489-503 (2010).
8. 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).
9. 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).
10. Laviad, E. L., Kelly, S., Merrill, A. H. Jr and Futerman, A. H. Modulation of ceramide synthase activity via dimerization. J. Biol. Chem. 287, 21025-21033 (2012).
11. Pewzner-Jung, Y., Ben-Dor, S. and 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).
12. Kraveka, J. M. et al. Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J. Biol. Chem. 282, 16718-16728 (2007).
13. 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).
14. Jennemann, R. et al. Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum. Mol. Genet. 21, 586-608 (2012).
15. 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).
16. Wijesinghe, D. S., Lamour, N. F., Gomez-Munoz, A. and Chalfant, C. E. Ceramide kinase and ceramide-1-phosphate. Methods Enzymol. 434, 265-292 (2007).
17. Huitema, K., van den Dikkenberg, J., Brouwers, J. F. and Holthuis, J. C. Identification of a family of animal sphingomyelin synthases. EMBO J. 23, 33-44 (2004).
18. 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).
19. D'Angelo, G. et al. Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi. Nature 501, 116-120 (2013).
20. Simanshu, D. K. et al. Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids. Nature 500, 463-467 (2013).
21. Maceyka, M. and Spiegel, S. Sphingolipid metabolites in inflammatory disease. Nature 510, 58-67 (2014).
22. 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).
23. Zamora-Pineda, J., Kumar, A., Suh, J. H., Zhang, M. and Saba, J. D. Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress. J. Exp. Med. 213, 2773-2791 (2016).
24. Sandhoff, K. Metabolic and cellular bases of sphingolipidoses. Biochem. Soc. Trans. 41, 562-568 (2013).
25. Rosenbloom, B. E. et al. Gaucher disease and cancer incidence: a study from the Gaucher Registry. Blood 105, 4569-4572 (2005).
26. 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).
27. Bode, H. et al. HSAN1 mutations in serine palmitoyltransferase reveal a close structure-functionphenotype relationship. Hum. Mol. Genet. 25, 853-865 (2016).
28. Kramer, R. et al. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. FASEB J. 29, 4461-4472 (2015).
29. Breslow, D. K. et al. Orm family proteins mediate sphingolipid homeostasis. Nature 463, 1048-1053 (2010).
30. Siow, D. L. and Wattenberg, B. W. Mammalian ORMDL proteins mediate the feedback response in ceramide biosynthesis. J. Biol. Chem. 287, 40198-40204 (2012).
31. 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).
32. 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).
33. Thomas, R. J. et al. HPV/E7 induces chemotherapymediated tumor suppression by ceramide-dependent mitophagy. EMBO Mol. Med. 9, 1030-1051 (2017).
34. Park, W. J. et al. Development of pheochromocytoma in ceramide synthase 2 null mice. Endocr. Relat. Cancer 22, 623-632 (2015).
35. 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).
36. 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).
37. Lee, H. et al. Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS ONE 6, e19783 (2011).
38. Jensen, S. A. et al. Bcl2L13 is a ceramide synthase inhibitor in glioblastoma. Proc. Natl Acad. Sci. USA 111, 5682-5687 (2014).
39. Senkal, C. E., Ponnusamy, S., Bielawski, J., Hannun, Y. A. and 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).
40. Suzuki, M. et al. Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells. J. Clin. Invest. 126, 254-265 (2016).
41. 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).
42. Schiffmann, S. et al. Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 30, 745-752 (2009).
43. Rahmaniyan, M. et al. Identification of dihydroceramide desaturase as a direct in vitro target for fenretinide. J. Biol. Chem. 286, 24754-24764 (2011).
44. 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).
45. Gorelik, A., Illes, K., Heinz, L. X., Superti-Furga, G. and Nagar, B. Crystal structure of mammalian acid sphingomyelinase. Nat. Commun. 7, 12196 (2016).
46. Santana, P. et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 86, 189-199 (1996).
47. Carpinteiro, A. et al. Regulation of hematogenous tumor metastasis by acid sphingomyelinase. EMBO Mol. Med. 7, 714-734 (2015).
48. Shamseddine, A. A. et al. P53-dependent upregulation of neutral sphingomyelinase-2: role in doxorubicin-induced growth arrest. Cell Death Dis. 6, e1947 (2015).
49. Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244-1247 (2008).
50. Chen, Y. et al. Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice. Mol. Cancer Ther. 14, 259-267 (2015).
51. 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).
52. Hanada, K. et al. Molecular machinery for nonvesicular trafficking of ceramide. Nature 426, 803-809 (2003).
53. 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).
54. Heering, J. et al. Loss of the ceramide transfer protein augments EGF receptor signaling in breast cancer. Cancer Res. 72, 2855-2866 (2012).
55. 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).
56. 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).
57. 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).
58. Payne, A. W., Pant, D. K., Pan, T. C. and Chodosh, L. A. Ceramide kinase promotes tumor cell survival and mammary tumor recurrence. Cancer Res. 74, 6352-6363 (2014).
59. 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).
60. 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).
61. Roh, J. L., Kim, E. H., Park, J. Y. and Kim, J. W. Inhibition of glucosylceramide synthase sensitizes head and neck cancer to cisplatin. Mol. Cancer Ther. 14, 1907-1915 (2015).
62. Stefanovic, M. et al. Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma. Oncotarget 7, 8253-8267 (2016).
63. Liu, Y. Y. et al. Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells. Cancer Res. 71, 2276-2285 (2011).
64. 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).
65. Eliyahu, E., Park, J. H., Shtraizent, N., He, X. and Schuchman, E. H. Acid ceramidase is a novel factor required for early embryo survival. FASEB J. 21, 1403-1409 (2007).
66. Cheng, J. C. et al. Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse. J. Clin. Invest. 123, 4344-4358 (2013).
67. Beckham, T. H. et al. Acid ceramidase induces sphingosine kinase 1/S1P receptor 2-mediated activation of oncogenic Akt signaling. Oncogenesis 2, e49 (2013).
68. 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).
69. Airola, M. V. et al. Structural basis for ceramide recognition and hydrolysis by human neutral ceramidase. Structure 23, 1482-1491 (2015).
70. Garcia-Barros, M. et al. Role of neutral ceramidase in colon cancer. FASEB J. 30, 4159-4171 (2016).
71. 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).
72. 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).
73. 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).
74. Xiong, Y., Yang, P., Proia, R. L. and Hla, T. Erythrocytederived sphingosine 1-phosphate is essential for vascular development. J. Clin. Invest. 124, 4823-4828 (2014).
75. Wang, Z. et al. Molecular basis of sphingosine kinase 1 substrate recognition and catalysis. Structure 21, 798-809 (2013).
76. Kawamori, T. et al. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 23, 405-414 (2009).
77. Zhang, Y. et al. Sphingosine kinase 1 and cancer: a systematic review and meta-analysis. PLoS ONE. 9, e90362 (2014).
78. Postepska-Igielska, A. et al. LncRNA Khps1 regulates expression of the proto-oncogene SPHK1 via triplexmediated changes in chromatin structure. Mol. Cell 60, 626-636 (2015).
79. Wang, Q. et al. Prognostic significance of sphingosine kinase 2 expression in non-small cell lung cancer. Tumour Biol. 35, 363-368 (2014).
80. Zhang, L., Liu, X., Zuo, Z., Hao, C. and Ma, Y. Sphingosine kinase 2 promotes colorectal cancer cell proliferation and invasion by enhancing MYC expression. Tumour Biol. 37, 8455-8460 (2016).
81. Hait, N. C., Bellamy, A., Milstien, S., Kordula, T. and Spiegel, S. Sphingosine kinase type 2 activation by ERK-mediated phosphorylation. J. Biol. Chem. 282, 12058-12065 (2007).
82. Degagne, E. et al. Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. J. Clin. Invest. 124, 5368-5384 (2014).
83. 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).
84. 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).
85. Obeid, L. M., Linardic, C. M., Karolak, L. A. and Hannun, Y. A. Programmed cell death induced by ceramide. Science 259, 1769-1771 (1993).
86. Siskind, L. J. et al. Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels. J. Biol. Chem. 283, 6622-6630 (2008).
87. Chang, K. T. et al. Ceramide channels: destabilization by Bcl-xL and role in apoptosis. Biochim. Biophys. Acta 1848, 2374-2384 (2015).
88. Chipuk, J. E. et al. Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell 148, 988-1000 (2012).
89. Blom, T. et al. LAPTM4B facilitates late endosomal ceramide export to control cell death pathways. Nat. Chem. Biol. 11, 799-806 (2015).
90. 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).
91. 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).
92. Saddoughi, S. A. and Ogretmen, B. Diverse functions of ceramide in cancer cell death and proliferation. Adv. Cancer Res. 117, 37-58 (2013).
93. Jiang, W. and Ogretmen, B. Autophagy paradox and ceramide. Biochim. Biophys. Acta 1841, 783-792 (2014).
94. Hernandez-Tiedra, S. et al. Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy 12, 2213-2229 (2016).
95. Corcelle-Termeau, E. et al. Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure. Autophagy 12, 833-849 (2016).
96. Sentelle, R. D. et al. Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat. Chem. Biol. 8, 831-838 (2012).
97. Dany, M. et al. Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML. Blood 128, 1944-1958 (2016).
98. 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).
99. Lepine, S., Allegood, J. C., Edmonds, Y., Milstien, S. and Spiegel, S. Autophagy induced by deficiency of sphingosine-1-phosphate phosphohydrolase 1 is switched to apoptosis by calpain-mediated autophagyrelated gene 5 (Atg5) cleavage. J. Biol. Chem. 286, 44380-44390 (2011).
100. Fekry, B., Esmaeilniakooshkghazi, A., Krupenko, S. A. and 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).
101. Heffernan-Stroud, L. A. et al. Defining a role for sphingosine kinase 1 in p53-dependent tumors. Oncogene 31, 1166-1175 (2012).
102. 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).
103. Pitson, S. M. et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J. 22, 5491-5500 (2003).
104. 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).
105. Hisano, Y., Kobayashi, N., Yamaguchi, A. and Nishi, T. Mouse SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial cells. PLoS ONE 7, e38941 (2012).
106. van der Weyden, L. et al. Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature 541, 233-236 (2017).
107. 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).
108. Visentin, B. et al. Validation of an antisphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages. Cancer Cell 9, 225-238 (2006).
109. 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).
110. 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).
111. 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).
112. 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).
113. Powell, J. A. et al. Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. Blood 129, 771-782 (2017).
114. 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).
115. 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).
116. Hirata, N. et al. Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligandindependent Notch activation. Nat. Commun. 5, 4806 (2014).
117. 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).
118. Ohotski, J. et al. Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptornegative breast cancer. Br. J. Cancer 106, 1453-1459 (2012).
119. Ohotski, J., Rosen, H., Bittman, R., Pyne, S. and 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).
120. Andrieu, G. et al. Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression. Sci Signal. 10, eaah4007 (2017).
121. Alvarez, S. E. et al. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465, 1084-1088 (2010).
122. Xiong, Y. et al. Sphingosine kinases are not required for inflammatory responses in macrophages. J. Biol. Chem. 288, 32563-32573 (2013).
123. 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).
124. 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).
125. Hait, N. C. et al. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325, 1254-1257 (2009).
126. 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).
127. 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).
128. Bose, R. et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82, 405-414 (1995).
129. 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).
130. 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).
131. Deng, X. et al. Ceramide biogenesis is required for radiation-induced apoptosis in the germ line of C. elegans. Science 322, 110-115 (2008).
132. Rotolo, J. et al. Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice. J. Clin. Invest. 122, 1786-1790 (2012).
133. Liu, Y. Y. et al. A role for ceramide in driving cancer cell resistance to doxorubicin. FASEB J. 22, 2541-2551 (2008).
134. Zhang, X. et al. Doxorubicin influences the expression of glucosylceramide synthase in invasive ductal breast cancer. PLoS ONE 7, e48492 (2012).
135. Rosa, R. et al. Sphingosine kinase 1 overexpression contributes to cetuximab resistance in human colorectal cancer models. Clin. Cancer Res. 19, 138-147 (2013).
136. 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).
137. Huang, X. et al. miRNA-95 mediates radioresistance in tumors by targeting the sphingolipid phosphatase SGPP1. Cancer Res. 73, 6972-6986 (2013).
138. 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).
139. 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).
140. Nair, S. et al. Clonal immunoglobulin against lysolipids in the origin of myeloma. N. Engl. J. Med. 374, 555-561 (2016).
141. Pandey, M. K. et al. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease. Nature 543, 108-112 (2017).
142. Sofi, M. H. et al. Ceramide synthesis regulates T cell activity and GVHD development. JCI Insight 2, e91701 (2017).
143. Le Nours, J. et al. Atypical natural killer T-cell receptor recognition of CD1d-lipid antigens. Nat. Commun. 7, 10570 (2016).
144. Lee, H. et al. STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nat. Med. 16, 1421-1428 (2010).
145. 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).
146. Garris, C. S. et al. Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat. Immunol. 14, 1166-1172 (2013).
147. Luo, B. et al. Erythropoeitin signaling in macrophages promotes dying cell clearance and immune tolerance. Immunity 44, 287-302 (2016).
148. Cohen, J. A. et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362, 402-415 (2010).
149. Kappos, L. et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362, 387-401 (2010).
150. Neviani, P. et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J. Clin. Invest. 123, 4144-4157 (2013).
151. Beljanski, V., Lewis, C. S. and Smith, C. D. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol. Ther. 11, 524-534 (2011).
152. 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).
153. 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).
154. 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).
155. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02834611 (2016).
156. 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).
157. 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).
158. Wang, J., Knapp, S., Pyne, N. J., Pyne, S. and Elkins, J. M. Crystal structure of sphingosine kinase 1 with PF-543. ACS Med. Chem. Lett. 5, 1329-1333 (2014).
159. Ju, T., Gao, D. and Fang, Z. Y. Targeting colorectal cancer cells by a novel sphingosine kinase 1 inhibitor PF-543. Biochem. Biophys. Res. Commun. 470, 728-734 (2016).
160. Kennedy, P. C. et al. Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J. Pharmacol. Exp. Ther. 338, 879-889 (2011).
161. 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).
162. 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).
163. Lewis, C. S., Voelkel-Johnson, C. and 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).
164. 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).
165. 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).
166. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02939807 (2016).
167. 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).
168. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02757326 (2016).
169. 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).
170. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02229981 (2014).
171. Bielawski, J. et al. Comprehensive quantitative analysis of bioactive sphingolipids by highperformance liquid chromatography-tandem mass spectrometry. Methods Mol. Biol. 579, 443-467 (2009).
172. 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).
173. Senkal, C. E. et al. Ceramide is metabolized to acylceramide and stored in lipid droplets. Cell Metab. 25, 686-697 (2017).
174. Russo, S. B., Tidhar, R., Futerman, A. H. and 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).
175. Menuz, V. et al. Protection of C. elegans from anoxia by HYL-2 ceramide synthase. Science 324, 381-384 (2009).
176. 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).