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Sphingolipid Metabolism in Cancer: Potential Therapeutic Target

  • Living reference work entry
  • First Online:
Handbook of Cancer and Immunology

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Abstract

Sphingolipids, particularly their two main bioactive metabolites ceramide and sphingosine-1-phosphate (S1P), play a key role in cancer death and survival. Ceramides induce cancer cell death through apoptosis, autophagy, or necroptosis. S1P on the other hand inhibits apoptosis and stimulates proliferation, migration, metastasis, and drug resistance via receptor-dependent or receptor-independent pathways. Modulating the cellular sphingolipidome, through targeting specific enzymes or metabolites, is emerging as a promising pharmacological intervention that could limit cancer progression and improve disease outcomes. In this chapter, we highlight new pharmacological tools that have the potential to modulate key sphingolipid enzymes and metabolites to be used in cancer treatment.

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References

  • Acebes-Fernández V, Landeria-Viñuela A, Juanes-Velasco P, Hernández AP, Otazo-Perez A, Manzano-Román R et al (2020) Nanomedicine and onco-immunotherapy: from the bench to bedside to biomarkers. Nanomaterials (Basel) 10(7)

    Google Scholar 

  • Acharya S, Yao J, Li P, Zhang C, Lowery FJ, Zhang Q et al (2019) Sphingosine kinase 1 signaling promotes metastasis of triple-negative breast cancer. Cancer Res 79(16):4211–4226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adachi K, Chiba K (2007) FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology. Perspect Med Chem 1:1177391X0700100002

    Google Scholar 

  • Adada MM, Canals D, Jeong N, Kelkar AD, Hernandez-Corbacho M, Pulkoski-Gross MJ et al (2015) Intracellular sphingosine kinase 2-derived sphingosine-1-phosphate mediates epidermal growth factor-induced ezrin-radixin-moesin phosphorylation and cancer cell invasion. FASEB J 29(11):4654–4669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aguilar A, Saba JD (2012) Truth and consequences of sphingosine-1-phosphate lyase. Adv Biol Regul 52(1):17–30

    Article  CAS  PubMed  Google Scholar 

  • Albi E, Magni MV (2008) Sphingolipid metabolism inhibitors and cell function. Open Enzyme Inhib J 1:72–79

    Article  CAS  Google Scholar 

  • Allam RM, Al-Abd AM, Khedr A, Sharaf OA, Nofal SM, Khalifa AE et al (2018) Fingolimod interrupts the cross talk between estrogen metabolism and sphingolipid metabolism within prostate cancer cells. Toxicol Lett 291:77–85

    Article  CAS  PubMed  Google Scholar 

  • Alvarez SE, Harikumar KB, Hait NC, Allegood J, Strub GM, Kim EY et al (2010) Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465(7301):1084–1088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andrieu G, Ledoux A, Branka S, Bocquet M, Gilhodes J, Walzer T et al (2017) Sphingosine 1-phosphate signaling through its receptor S1P5 promotes chromosome segregation and mitotic progression. Sci Signal 10(472)

    Google Scholar 

  • Antoon JW, White MD, Meacham WD, Slaughter EM, Muir SE, Elliott S et al (2010) Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology 151(11):5124–5135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Antoon JW, White MD, Burow ME, Beckman BS (2012) Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance. Oncol Rep 27(6):1779–1786

    CAS  PubMed  Google Scholar 

  • Aoki H, Aoki M, Katsuta E, Mukhopadhyay P, Yang J, Zhou H et al (2016) Conjugated bile acids aggravate metastatic pancreatic cancer via sphingosine-1-phosphate receptor 2. AACR

    Google Scholar 

  • Ardestani S, Deskins DL, Young PP (2013) Membrane TNF-alpha-activated programmed necrosis is mediated by Ceramide-induced reactive oxygen species. J Mol Signal 8:12

    Article  PubMed  PubMed Central  Google Scholar 

  • Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science:1305–1308

    Google Scholar 

  • Becker KA, Beckmann N, Adams C, Hessler G, Kramer M, Gulbins E et al (2017) Melanoma cell metastasis via P-selectin-mediated activation of acid sphingomyelinase in platelets. Clin Exp Metastasis 34(1):25–35

    Article  CAS  PubMed  Google Scholar 

  • Beckham TH, Elojeimy S, Cheng JC, Turner LS, Hoffman SR, Norris JS et al (2010) Targeting sphingolipid metabolism in head and neck cancer: rational therapeutic potentials. Expert Opin Ther Targets 14(5):529–539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beljanski V, Knaak C, Zhuang Y, Smith CD (2011) Combined anticancer effects of sphingosine kinase inhibitors and sorafenib. Investig New Drugs 29(6):1132–1142

    Article  CAS  Google Scholar 

  • Bexiga C, Nejo P, Oliveira I, Rodrigues P, Pereira P, Fragoso S et al (eds) (2020) When BRCA2-breast cancer is more prevalent than BRCA1-breast cancer: prospective follow-up data from a multidisciplinary program. Cancer research. American Association for Cancer Research, Philadelphia

    Google Scholar 

  • Bhargava S, Hotz B, Hines OJ, Reber HA, Buhr HJ, Hotz HG (2007) Suramin inhibits not only tumor growth and metastasis but also angiogenesis in experimental pancreatic cancer. J Gastrointest Surg 11(2):171–178

    Article  PubMed  Google Scholar 

  • Bi Y, Li J, Ji B, Kang N, Yang L, Simonetto DA et al (2014) Sphingosine-1-phosphate mediates a reciprocal signaling pathway between stellate cells and cancer cells that promotes pancreatic cancer growth. Am J Pathol 184(10):2791–2802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bieberich E, Kawaguchi T, Robert KY (2000) N-acylated serinol is a novel ceramide mimic inducing apoptosis in neuroblastoma cells. J Biol Chem 275(1):177–181

    Article  CAS  PubMed  Google Scholar 

  • Birbes H, El Bawab S, Hannun YA, Obeid LM (2001) Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. FASEB J 15(14):2669–2679

    Article  CAS  PubMed  Google Scholar 

  • Birbes H, El Bawab S, Obeid LM, Hannun YA (2002) Mitochondria and ceramide: intertwined roles in regulation of apoptosis. Adv Enzym Regul 42:113–129

    Article  CAS  Google Scholar 

  • Birbes H, Luberto C, Hsu Y-T, El Bawab S, Hannun YA, Obeid LM (2005) A mitochondrial pool of sphingomyelin is involved in TNFα-induced Bax translocation to mitochondria. Biochem J 386(3):445–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bleicher RJ, Cabot MC (2002) Glucosylceramide synthase and apoptosis. Biochim Biophys Acta 1585(2-3):172–178

    Article  CAS  PubMed  Google Scholar 

  • Bradley E, Dasgupta S, Jiang X, Zhao X, Zhu G, He Q et al (2014) Critical role of Spns2, a sphingosine-1-phosphate transporter, in lung cancer cell survival and migration. PLoS One 9(10):e110119

    Article  PubMed  PubMed Central  Google Scholar 

  • Breen P, Joseph N, Thompson K, Kraveka JM, Gudz TI, Li L et al (2013) Dihydroceramide desaturase knockdown impacts sphingolipids and apoptosis after photodamage in human head and neck squamous carcinoma cells. Anticancer Res 33(1):77–84

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bu Y, Wu H, Deng R, Wang Y (2021) Therapeutic potential of SphK1 inhibitors based on abnormal expression of SphK1 in inflammatory immune related-diseases. Front Pharmacol 2872

    Google Scholar 

  • Bursch W, Ellinger A, Kienzl H, Török L, Pandey S, Sikorska M et al (1996) Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 17(8):1595–1607

    Article  CAS  PubMed  Google Scholar 

  • Cai H, Xie X, Ji L, Ruan X, Zheng Z (2017) Sphingosine kinase 1: a novel independent prognosis biomarker in hepatocellular carcinoma. Oncol Lett 13(4):2316–2322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Camacho L, Ouro A, Gomez-Larrauri A, Carracedo A, Gomez-Muñoz A (2022) Implication of ceramide kinase/C1P in cancer development and progression. Cancer 14(1):227

    Article  CAS  Google Scholar 

  • Camerini T, Mariani L, De Palo G, Marubini E, Di Mauro MG, Decensi A et al (2001) Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer. J Clin Oncol 19(6):1664–1670

    Article  CAS  PubMed  Google Scholar 

  • Cao M, Ji C, Zhou Y, Huang W, Ni W, Tong X et al (2018) Sphingosine kinase inhibitors: a patent review. Int J Mol Med 41(5):2450–2460

    CAS  PubMed  Google Scholar 

  • Carfagna MA, Young KM, Susick RL (1996) Sex differences in rat hepatic cytolethality of the protein kinase C inhibitor safingol: role of biotransformation. Toxicol Appl Pharmacol 137(2):173–181

    Article  CAS  PubMed  Google Scholar 

  • Chang WW, Lee CH, Lee P, Lin J, Hsu CW, Hung JT et al (2008) Expression of Globo H and SSEA3 in breast cancer stem cells and the involvement of fucosyl transferases 1 and 2 in Globo H synthesis. Proc Natl Acad Sci U S A 105(33):11667–11672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang C-L, Ho M-C, Lee P-H, Hsu C-Y, Huang W-P, Lee H (2009) S1P5 is required for sphingosine 1-phosphate-induced autophagy in human prostate cancer PC-3 cells. Am J Physiol Cell Physiol 297(2):C451–C4C8

    Article  CAS  PubMed  Google Scholar 

  • Chapman JV, GouazĂ©-Andersson V, Cabot MC (2010) Expression of P-glycoprotein in HeLa cells confers resistance to ceramide cytotoxicity. Int J Oncol 37(6):1591–1597

    CAS  PubMed  Google Scholar 

  • Chen K, Pan Q, Gao Y, Yang X, Wang S, Peppelenbosch MP et al (2014) DMS triggers apoptosis associated with the inhibition of SPHK1/NF-ÎşB activation and increase in intracellular Ca2+ concentration in human cancer cells. Int J Mol Med 33(1):17–24

    Article  CAS  PubMed  Google Scholar 

  • Cheng B, Gao F, Maissy E, Xu P (2019) Repurposing suramin for the treatment of breast cancer lung metastasis with glycol chitosan-based nanoparticles. Acta Biomater 84:378–390

    Article  CAS  PubMed  Google Scholar 

  • Cheung E, Pinski J, Dorff T, Groshen S, Quinn DI, Reynolds CP et al (2009) Oral fenretinide in biochemically recurrent prostate cancer: a California cancer consortium phase II trial. Clin Genitourin Cancer 7(1):43–50

    Article  CAS  PubMed  Google Scholar 

  • Chiba K, Yanagawa Y, Masubuchi Y, Kataoka H, Kawaguchi T, Ohtsuki M et al (1998) FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol 160(10):5037–5044

    Article  CAS  PubMed  Google Scholar 

  • Chua CW, Lee DT, Ling MT, Zhou C, Man K, Ho J et al (2005) FTY720, a fungus metabolite, inhibits in vivo growth of androgen-independent prostate cancer. Int J Cancer 117(6):1039–1048

    Article  CAS  PubMed  Google Scholar 

  • Chumanevich AA, Poudyal D, Cui X, Davis T, Wood PA, Smith CD et al (2010) Suppression of colitis-driven colon cancer in mice by a novel small molecule inhibitor of sphingosine kinase. Carcinogenesis 31(10):1787–1793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • ClinicalTrials.gov. Suramin in Treating Patients With Recurrent Bladder Cancer 2013. Updated June 26, 2013. Available from: https://clinicaltrials.gov/ct2/show/NCT00006476

  • Companioni O, Mir C, Garcia-Mayea Y, ME LL. (2021) Targeting sphingolipids for cancer therapy. Front Oncol 11:745092

    Article  PubMed  PubMed Central  Google Scholar 

  • Cook KL, Shajahan AN, Wärri A, Jin L, Hilakivi-Clarke LA, Clarke R (2012) Glucose-regulated protein 78 controls cross-talk between apoptosis and autophagy to determine antiestrogen responsiveness. Cancer Res 72(13):3337–3349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • CristĂłbal I, Manso R, RincĂłn R, CaramĂ©s C, Senin C, Borrero A et al (2014) PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential. Mol Cancer Ther 13(4):938–947

    Article  PubMed  Google Scholar 

  • Dai L, Liu Y, Xie L, Wu X, Qiu L, Di W (2017) Sphingosine kinase 1/sphingosine-1-phosphate (S1P)/S1P receptor axis is involved in ovarian cancer angiogenesis. Oncotarget 8(43):74947

    Article  PubMed  PubMed Central  Google Scholar 

  • Dai L, Chen J, Lin Z, Wang Z, Mu S, Qin Z (2020) Targeting sphingosine kinase by ABC294640 against Diffuse Intrinsic Pontine Glioma (DIPG). J Cancer 11(16):4683–4691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S (2004) Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 64(12):4286–4293

    Article  CAS  PubMed  Google Scholar 

  • Davis MD, Clemens JJ, Macdonald TL, Lynch KR (2005) Sphingosine 1-phosphate analogs as receptor antagonists. J Biol Chem 280(11):9833–9841

    Article  CAS  PubMed  Google Scholar 

  • Dbaibo GS, Perry DK, Gamard CJ, Platt R, Poirier GG, Obeid LM et al (1997) Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-α: CrmA and Bcl-2 target distinct components in the apoptotic pathway. J Exp Med 185(3):481–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dbaibo GS, El-Assaad W, Krikorian A, Liu B, Diab K, Idriss NZ et al (2001) Ceramide generation by two distinct pathways in tumor necrosis factor α-induced cell death. FEBS Lett 503(1):7–12

    Article  CAS  PubMed  Google Scholar 

  • DegagnĂ© E, Saba JD (2014) S1pping fire: Sphingosine-1-phosphate signaling as an emerging target in inflammatory bowel disease and colitis-associated cancer. Clin Exp Gastroenterol 7:205

    PubMed  PubMed Central  Google Scholar 

  • DegagnĂ© E, Pandurangan A, Bandhuvula P, Kumar A, Eltanawy A, Zhang M et al (2014) Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. J Clin Invest 124(12):5368–5384

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Scala C, Mazzarino M, Yahi N, Varini K, Garmy N, Fantini J et al (2017) Ceramide binding to anandamide increases its half-life and potentiates its cytotoxicity in human neuroblastoma cells. Chem Phys Lipids 205:11–17

    Article  PubMed  Google Scholar 

  • Dick TE, Hengst JA, Fox TE, Colledge AL, Kale VP, Sung SS et al (2015) The apoptotic mechanism of action of the sphingosine kinase 1 selective inhibitor SKI-178 in human acute myeloid leukemia cell lines. J Pharmacol Exp Ther 352(3):494–508

    Article  PubMed  PubMed Central  Google Scholar 

  • Dickson MA, Carvajal RD, Merrill AH Jr, Gonen M, Cane LM, Schwartz GK (2011) A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors. Clin Cancer Res 17(8):2484–2492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doronin II, Vishnyakova PA, Kholodenko IV, Ponomarev ED, Ryazantsev DY, Molotkovskaya IM et al (2014) Ganglioside GD2 in reception and transduction of cell death signal in tumor cells. BMC Cancer 14:295

    Article  PubMed  PubMed Central  Google Scholar 

  • Duan R-D (2006) Alkaline sphingomyelinase: an old enzyme with novel implications. Biochimica et Biophysica Acta (BBA) Mol Cell Biol Lipids 1761(3):281–291

    Article  CAS  Google Scholar 

  • Dumitru C, Gulbins E (2006) TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 25(41):5612–5625

    Article  CAS  PubMed  Google Scholar 

  • Ekiz HA, Baran Y (2010) Therapeutic applications of bioactive sphingolipids in hematological malignancies. Int J Cancer 127(7):1497–1506

    Article  CAS  PubMed  Google Scholar 

  • Erez-Roman R, Pienik R, Futerman AH (2010) Increased ceramide synthase 2 and 6 mRNA levels in breast cancer tissues and correlation with sphingosine kinase expression. Biochem Biophys Res Commun 391(1):219–223

    Article  CAS  PubMed  Google Scholar 

  • Ertao Z, Jianhui C, Kang W, Zhijun Y, Hui W, Chuangqi C et al (2016) Prognostic value of mixed lineage kinase domain-like protein expression in the survival of patients with gastric cancer. Tumor Biol 37(10):13679–13685

    Article  Google Scholar 

  • Fan SH, Wang YY, Lu J, Zheng YL, Wu DM, Zhang ZF et al (2015) CERS2 suppresses tumor cell invasion and is associated with decreased V-ATPase and MMP-2/MMP-9 activities in breast cancer. J Cell Biochem 116(4):502–513

    Article  CAS  PubMed  Google Scholar 

  • Fekry B, Jeffries KA, Esmaeilniakooshkghazi A, Ogretmen B, Krupenko SA, Krupenko NI (2016) CerS6 is a novel transcriptional target of p53 protein activated by non-genotoxic stress. J Biol Chem 291(32):16586–16596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • French KJ, Schrecengost RS, Lee BD, Zhuang Y, Smith SN, Eberly JL et al (2003) Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 63(18):5962–5969

    CAS  PubMed  Google Scholar 

  • French KJ, Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V et al (2010) Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther 333(1):129–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Futerman AH, Hannun YA (2004) The complex life of simple sphingolipids. EMBO Rep 5(8):777–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gamard CJ, Dbaibo GS, Liu B, Obeid LM, Hannun YA (1997) Selective involvement of ceramide in cytokine-induced apoptosis: ceramide inhibits phorbol ester activation of nuclear factor ÎşB. J Biol Chem 272(26):16474–16481

    Article  CAS  PubMed  Google Scholar 

  • GarcĂ­a-Ruiz C, Colell A, MarĂ­ M, Morales A, Fernández-Checa JC (1997) Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species: role of mitochondrial glutathione. J Biol Chem 272(17):11369–11377

    Article  PubMed  Google Scholar 

  • Gasser O, Sharples KJ, Barrow C, Williams GM, Bauer E, Wood CE et al (2018) A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients. Cancer Immunol Immunother 67(2):285–298

    Article  CAS  PubMed  Google Scholar 

  • Gong Y, Fan Z, Luo G, Yang C, Huang Q, Fan K et al (2019) The role of necroptosis in cancer biology and therapy. Mol Cancer 18(1):1–17

    Article  CAS  Google Scholar 

  • González-Fernández B, Sánchez DI, González-Gallego J, Tuñón MJ (2017) Sphingosine 1-phosphate signaling as a target in hepatic fibrosis therapy. Front Pharmacol 8:579

    Article  PubMed  PubMed Central  Google Scholar 

  • GouazĂ© V, Yu JY, Bleicher RJ, Han TY, Liu YY, Wang H et al (2004) Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy. Mol Cancer Ther 3(5):633–639

    Article  PubMed  Google Scholar 

  • Gozuacik D, Kimchi A (2007) Autophagy and cell death. Curr Top Dev Biol 78:217–245

    Article  CAS  PubMed  Google Scholar 

  • GrbÄŤić P, Car EP, Sedić M (2020) Targeting ceramide metabolism in hepatocellular carcinoma: new points for therapeutic intervention. Curr Med Chem 27(39):6611–6627

    Article  PubMed  Google Scholar 

  • Gudz TI, Tserng K-Y, Hoppel CL (1997) Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem 272(39):24154–24158

    Article  CAS  PubMed  Google Scholar 

  • Guillermet-Guibert J, Davenne L, Pchejetski D, Saint-Laurent N, Brizuela L, Guilbeau-Frugier C et al (2009) Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug. Mol Cancer Ther 8(4):809–820

    Article  CAS  PubMed  Google Scholar 

  • Gump JM, Staskiewicz L, Morgan MJ, Bamberg A, Riches DW, Thorburn A (2014) Autophagy variation within a cell population determines cell fate through selective degradation of Fap-1. Nat Cell Biol 16(1):47–54

    Article  CAS  PubMed  Google Scholar 

  • Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM et al (2013) Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev 27(13):1447–1461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta P, Taiyab A, Hussain A, Alajmi MF, Islam A, Hassan MI (2021) Targeting the sphingosine kinase/sphingosine-1-phosphate signaling axis in drug discovery for cancer therapy. Cancers (Basel) 13(8)

    Google Scholar 

  • Haberl EM, Pohl R, Rein-Fischboeck L, Höring M, Krautbauer S, Liebisch G et al (2021) Accumulation of cholesterol, triglycerides and ceramides in hepatocellular carcinomas of diethylnitrosamine injected mice. Lipids Health Dis 20(1):1–14

    Article  Google Scholar 

  • Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK et al (2009) Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science 325(5945):1254–1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hait NC, Avni D, Yamada A, Nagahashi M, Aoyagi T, Aoki H et al (2015) The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer. Oncogenesis 4(6):e156-e

    Article  Google Scholar 

  • Hamada M, Wakabayashi K, Masui A, Iwai S, Imai T, Yura Y (2014) Involvement of hydrogen peroxide in safingol-induced endonuclease G-mediated apoptosis of squamous cell carcinoma cells. Int J Mol Sci 15(2):2660–2671

    Article  PubMed  PubMed Central  Google Scholar 

  • Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F et al (2009) Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci 106(20):8186–8191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M et al (2003) Molecular machinery for non-vesicular trafficking of ceramide. Nature 426(6968):803–809

    Article  CAS  PubMed  Google Scholar 

  • Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9(2):139–150

    Article  CAS  PubMed  Google Scholar 

  • Heakal Y, Kester M (2009) Nanoliposomal short-chain ceramide inhibits agonist-dependent translocation of neurotensin receptor 1 to structured membrane microdomains in breast cancer cells. Mol Cancer Res 7(5):724–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heiner JP, Miraldi F, Kallick S, Makley J, Neely J, Smith-Mensah WH et al (1987) Localization of GD2-specific monoclonal antibody 3F8 in human osteosarcoma. Cancer Res 47(20):5377–5381

    CAS  PubMed  Google Scholar 

  • Hengst JA, Dick TE, Sharma A, Doi K, Hegde S, Tan SF et al (2017) SKI-178: a multitargeted inhibitor of sphingosine kinase and microtubule dynamics demonstrating therapeutic efficacy in acute myeloid leukemia models. Cancer Transl Med 3(4):109–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hii L-W, Chung FF-L, Mai C-W, Ng PY, Leong C-O (2021) Sphingosine kinase 1 signaling in breast cancer: a potential target to tackle breast cancer stem cells. Front Mol Biosci:8

    Google Scholar 

  • Hirata N, Yamada S, Shoda T, Kurihara M, Sekino Y, Kanda Y (2014) Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation. Nat Commun 5(1):1–14

    Article  Google Scholar 

  • Hu W-M, Li L, Jing B-Q, Zhao Y-S, Wang C-L, Feng L et al (2010) Effect of S1P5 on proliferation and migration of human esophageal cancer cells. World J Gastroenterol 16(15):1859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang C-S, Yu AL, Tseng L-M, Chow LW, Hou M-F, Hurvitz SA et al (2016) Randomized phase II/III trial of active immunotherapy with OPT-822/OPT-821 in patients with metastatic breast cancer. Am Soc Clin Oncol

    Book  Google Scholar 

  • Huitema K, van den Dikkenberg J, Brouwers JF, Holthuis JC (2004) Identification of a family of animal sphingomyelin synthases. EMBO J 23(1):33–44

    Article  CAS  PubMed  Google Scholar 

  • Jennemann R, Rabionet M, Gorgas K, Epstein S, Dalpke A, Rothermel U et al (2012) Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum Mol Genet 21(3):586–608

    Article  CAS  PubMed  Google Scholar 

  • Jiao Y, Hc WANG, Sj FAN (2007) Growth suppression and radiosensitivity increase by HMGB1 in breast cancer 1. Acta Pharmacol Sin 28(12):1957–1967

    Article  CAS  PubMed  Google Scholar 

  • Kale J, Osterlund EJ, Andrews DW (2018) BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ 25(1):65–80

    Article  CAS  PubMed  Google Scholar 

  • Kalhori V, Magnusson M, Asghar MY, Pulli I, Törnquist K (2016) FTY720 (Fingolimod) attenuates basal and sphingosine-1-phosphate-evoked thyroid cancer cell invasion. Endocr Relat Cancer 23(5):457–468

    Article  CAS  PubMed  Google Scholar 

  • Kang R, Zhang Q, Zeh HJ, Lotze MT, Tang D (2013) HMGB1 in cancer: good, bad, or both? Clin Cancer Res 19(15):4046–4057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karahatay S, Thomas K, Koybasi S, Senkal CE, ElOjeimy S, Liu X et al (2007) Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): attenuation of C18-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis. Cancer Lett 256(1):101–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kartal-Yandim M, Adan-Gokbulut A, Baran Y (2016) Molecular mechanisms of drug resistance and its reversal in cancer. Crit Rev Biotechnol 36(4):716–726

    Article  CAS  PubMed  Google Scholar 

  • Kashkar H, Wiegmann K, Yazdanpanah B, Haubert D, Krönke M (2005) Acid sphingomyelinase is indispensable for UV light-induced Bax conformational change at the mitochondrial membrane. J Biol Chem 280(21):20804–20813

    Article  CAS  PubMed  Google Scholar 

  • Kawamori T, Kaneshiro T, Okumura M, Maalouf S, Uflacker A, Bielawski J et al (2009) Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J 23(2):405–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawanabe T, Kawakami T, Yatomi Y, Shimada S, Soma Y (2007) Sphingosine 1-phosphate accelerates wound healing in diabetic mice. J Dermatol Sci 48(1):53–60

    Article  CAS  PubMed  Google Scholar 

  • Kennedy L, Alpini G (2018) Therapeutic role of sphingosine-1-phosphate receptor 2 in the progression of esophageal adenocarcinoma. Am J Pathol 188(9):1949–1952

    Article  CAS  PubMed  Google Scholar 

  • Kennedy PC, Zhu R, Huang T, Tomsig JL, Mathews TP, David M et al (2011) Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J Pharmacol Exp Ther 338(3):879–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khiste SK, Liu Z, Roy KR, Uddin MB, Hosain SB, Gu X et al (2020) Ceramide–rubusoside nanomicelles, a potential therapeutic approach to target cancers carrying p53 missense mutations. Mol Cancer Ther 19(2):564–574

    Article  CAS  PubMed  Google Scholar 

  • Kim WJ, Okimoto RA, Purton LE, Goodwin M, Haserlat SM, Dayyani F et al (2008) Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood J Am Soc Hematol 111(9):4716–4722

    CAS  Google Scholar 

  • Kitatani K, Idkowiak-Baldys J, Hannun YA (2008) The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 20(6):1010–1018

    Article  CAS  PubMed  Google Scholar 

  • Kolesnick R (2002) The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J Clin Investig 110(1):3–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kondo Y, Kondo S (2006) Autophagy and cancer therapy. Autophagy 2(2):85–90

    Article  PubMed  Google Scholar 

  • Kornhuber J, Rhein C, MĂĽller CP, MĂĽhle C (2015) Secretory sphingomyelinase in health and disease. Biol Chem 396(6-7):707–736

    Article  CAS  PubMed  Google Scholar 

  • Kotlyarov S, Kotlyarova A (2021) The role of ABC transporters in lipid metabolism and the comorbid course of chronic obstructive pulmonary disease and atherosclerosis. Int J Mol Sci 22(13):6711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kowalczyk A, Gil M, Horwacik I, Odrowaz Z, Kozbor D, Rokita H (2009) The GD2-specific 14G2a monoclonal antibody induces apoptosis and enhances cytotoxicity of chemotherapeutic drugs in IMR-32 human neuroblastoma cells. Cancer Lett 281(2):171–182

    Article  CAS  PubMed  Google Scholar 

  • Koybasi S, Senkal CE, Sundararaj K, Spassieva S, Bielawski J, Osta W et al (2004) 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(43):44311–44319

    Article  CAS  PubMed  Google Scholar 

  • Kraveka JM, Li L, Szulc ZM, Bielawski J, Ogretmen B, Hannun YA et al (2007) Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J Biol Chem 282(23):16718–16728

    Article  CAS  PubMed  Google Scholar 

  • Kreitzburg KM, van Waardenburg RC, Yoon KJ (2018) Sphingolipid metabolism and drug resistance in ovarian cancer. Cancer Drug Resistance (Alhambra, Calif) 1:181

    PubMed  Google Scholar 

  • Kumar A, Zamora-Pineda J, DegagnĂ© E, Saba JD (2017) S1P lyase regulation of thymic egress and oncogenic inflammatory signaling. Mediat Inflamm 2017:7685142

    Article  Google Scholar 

  • Kummar S, Gutierrez ME, Maurer BJ, Reynolds CP, Kang M, Singh H et al (2011) Phase I trial of fenretinide lym-x-sorb oral powder in adults with solid tumors and lymphomas. Anticancer Res 31(3):961–966

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kuniyasu H, Oue N, Wakikawa A, Shigeishi H, Matsutani N, Kuraoka K et al (2002) Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J Pathol 196(2):163–170

    Article  CAS  PubMed  Google Scholar 

  • Lachkar F, FerrĂ© P, Foufelle F, Papaioannou A (2021) Dihydroceramides: their emerging physiological roles and functions in cancer and metabolic diseases. Am J Physiol Endocrinol Metab 320(1):E122–EE30

    Article  CAS  PubMed  Google Scholar 

  • Ladisch S, Becker H, Ulsh L (1992) Immunosuppression by human gangliosides: I. Relationship of carbohydrate structure to the inhibition of T cell responses. Biochim Biophys Acta 1125(2):180–188

    Article  CAS  PubMed  Google Scholar 

  • Lamb YN (2020) Ozanimod: first approval. Drugs 80(8):841–848

    Article  CAS  PubMed  Google Scholar 

  • LaMontagne K, Littlewood-Evans A, Schnell C, O’Reilly T, Wyder L, Sanchez T et al (2006) Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization. Cancer Res 66(1):221–231

    Article  CAS  PubMed  Google Scholar 

  • Lankadasari MB, Aparna JS, Mohammed S, James S, Aoki K, Binu VS et al (2018) Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine. Theranostics 8(14):3824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lavie Y, Cao H-T, Bursten SL, Giuliano AE, Cabot MC (1996) Accumulation of glucosylceramides in multidrug-resistant cancer cells. J Biol Chem 271(32):19530–19536

    Article  CAS  PubMed  Google Scholar 

  • Lee YS, Choi KM, Choi MH, Ji SY, Lee S, Sin DM et al (2011) Serine palmitoyltransferase inhibitor myriocin induces growth inhibition of B16F10 melanoma cells through G2/M phase arrest. Cell Prolif 44(4):320–329

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee AJ, Roylance R, Sander J, Gorman P, Endesfelder D, Kschischo M et al (2012) CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction. J Pathol 226(3):482–494

    Article  CAS  PubMed  Google Scholar 

  • LeĂłn Y, Magariños M, Varela-Nieto I (2021) Ceramide kinase inhibition blocks IGF-1-mediated survival of otic neurosensory progenitors by impairing AKT phosphorylation. Front Cell Dev Biol 9:1437

    Article  Google Scholar 

  • Leroux M, Auzenne E, Evans R, Hail N Jr, Spohn W, Ghosh S et al (2007) Sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells. Prostate 67(15):1699–1717

    Article  CAS  PubMed  Google Scholar 

  • Levy JMM, Thorburn A (2011) Targeting autophagy during cancer therapy to improve clinical outcomes. Pharmacol Ther 131(1):130–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li M-H, Sanchez T, Milne GL, Morrow JD, Hla T, Ferrer F (2009a) S1P/S1P2 signaling induces cyclooxygenase-2 expression in Wilms tumor. J Urol 181(3):1347–1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li C, Jiang X, Yang L, Liu X, Yue S, Li L (2009b) Involvement of sphingosine 1-phosphate (SIP)/S1P3 signaling in cholestasis-induced liver fibrosis. Am J Pathol 175(4):1464–1472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li H, Li H, Qu H, Zhao M, Yuan B, Cao M et al (2015) Suramin inhibits cell proliferation in ovarian and cervical cancer by downregulating heparanase expression. Cancer Cell Int 15(1):1–11

    Article  Google Scholar 

  • Li G, Liu D, Kimchi ET, Kaifi JT, Qi X, Manjunath Y et al (2018) Nanoliposome C6-ceramide increases the anti-tumor immune response and slows growth of liver tumors in mice. Gastroenterology 154(4):1024–1036. e9

    Article  CAS  PubMed  Google Scholar 

  • Ling LU, Lin H, Tan KB, Chiu GN (2009) The role of protein kinase C in the synergistic interaction of safingol and irinotecan in colon cancer cells. Int J Oncol 35(6):1463–1471

    CAS  PubMed  Google Scholar 

  • Ling LU, Tan KB, Lin H, Chiu GN (2011) The role of reactive oxygen species and autophagy in safingol-induced cell death. Cell Death Dis 2(3):e129

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu L, Yang M, Kang R, Wang Z, Zhao Y, Yu Y et al (2011) HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. Leukemia 25(1):23–31

    Article  PubMed  Google Scholar 

  • Liu YY, Hill RA, Li YT (2013) Ceramide glycosylation catalyzed by glucosylceramide synthase and cancer drug resistance. Adv Cancer Res 117:59–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu R, Zhao R, Zhou X, Liang X, Campbell DJ, Zhang X et al (2014) Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2. Hepatology 60(3):908–918

    Article  CAS  PubMed  Google Scholar 

  • Liu R, Li X, Qiang X, Luo L, Hylemon PB, Jiang Z et al (2015) Taurocholate induces cyclooxygenase-2 expression via the sphingosine 1-phosphate receptor 2 in a human cholangiocarcinoma cell line. J Biol Chem 290(52):30988–31002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu R, Li X, Hylemon PB, Zhou H (2018) Conjugated bile acids promote invasive growth of esophageal adenocarcinoma cells and cancer stem cell expansion via sphingosine 1-phosphate receptor 2–mediated Yes-associated protein activation. Am J Pathol 188(9):2042–2058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, Ni C, Zhang D, Sun H, Dong X, Che N et al (2019) S1PR1 regulates the switch of two angiogenic modes by VE-cadherin phosphorylation in breast cancer. Cell Death Dis 10(3):1–15

    Article  Google Scholar 

  • Long JS, Edwards J, Watson C, Tovey S, Mair KM, Schiff R et al (2010) Sphingosine kinase 1 induces tolerance to human epidermal growth factor receptor 2 and prevents formation of a migratory phenotype in response to sphingosine 1-phosphate in estrogen receptor-positive breast cancer cells. Mol Cell Biol 30(15):3827–3841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maceyka M, Spiegel S (2014) Sphingolipid metabolites in inflammatory disease. Nature 510(7503):58–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maceyka M, Rohrbach T, Milstien S, Spiegel S (2019) Role of sphingosine kinase 1 and sphingosine-1-phosphate axis in hepatocellular carcinoma. In: Lipid signaling in human diseases. Springer, pp 3–17

    Chapter  Google Scholar 

  • Magaye RR, Savira F, Hua Y, Kelly DJ, Reid C, Flynn B et al (2019) The role of dihydrosphingolipids in disease. Cell Mol Life Sci 76(6):1107–1134

    Article  CAS  PubMed  Google Scholar 

  • Marmonti E, Savage H, Zhang A, Bedoya CA, Morrell MG, Harden A et al (2020) Modulating sphingosine-1-phosphate receptors to improve chemotherapy efficacy against Ewing sarcoma. Int J Cancer 147(4):1206–1214

    Article  CAS  PubMed  Google Scholar 

  • Matarrese P, Garofalo T, Manganelli V, Gambardella L, Marconi M, Grasso M et al (2014) Evidence for the involvement of GD3 ganglioside in autophagosome formation and maturation. Autophagy 10(5):750–765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mattner J, Debord KL, Ismail N, Goff RD, Cantu C 3rd, Zhou D et al (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434(7032):525–529

    Article  CAS  PubMed  Google Scholar 

  • Matula K, Collie-Duguid E, Murray G, Parikh K, Grabsch H, Tan P et al (2015) Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer. BMC Cancer 15:762

    Article  PubMed  PubMed Central  Google Scholar 

  • Meyers-Needham M, Ponnusamy S, Gencer S, Jiang W, Thomas RJ, Senkal CE et al (2012) Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells. EMBO Mol Med 4(2):78–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Modica-Napolitano JS, Aprille JR (2001) Delocalized lipophilic cations selectively target the mitochondria of carcinoma cells. Adv Drug Deliv Rev 49(1-2):63–70

    Article  CAS  PubMed  Google Scholar 

  • Modrak DE, Cardillo TM, Newsome GA, Goldenberg DM, Gold DV (2004) Synergistic interaction between sphingomyelin and gemcitabine potentiates ceramide-mediated apoptosis in pancreatic cancer. Cancer Res 64(22):8405–8410

    Article  CAS  PubMed  Google Scholar 

  • Morad SA, Levin JC, Shanmugavelandy SS, Kester M, Fabrias G, Bedia C et al (2012) Ceramide–antiestrogen nanoliposomal combinations – novel impact of hormonal therapy in hormone-insensitive breast cancer. Mol Cancer Ther 11(11):2352–2361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morales A, Lee H, Goñi FM, Kolesnick R, Fernandez-Checa JC (2007a) Sphingolipids and cell death. Apoptosis 12(5):923–939

    Article  CAS  PubMed  Google Scholar 

  • Morales A, ParĂ­s R, Villanueva A, Llacuna L, GarcĂ­a-Ruiz C, Fernández-Checa JC (2007b) Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo. Oncogene 26(6):905–916

    Article  CAS  PubMed  Google Scholar 

  • Morales PR, Dillehay DL, Moody SJ, Pallas DC, Pruett S, Allgood JC et al (2007c) Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation. Drug Chem Toxicol 30(3):197–216

    Article  CAS  PubMed  Google Scholar 

  • Moro K, Kawaguchi T, Tsuchida J, Gabriel E, Qi Q, Yan L et al (2018) Ceramide species are elevated in human breast cancer and are associated with less aggressiveness. Oncotarget 9(28):19874

    Article  PubMed  PubMed Central  Google Scholar 

  • Mousseau Y, Mollard S, Faucher-Durand K, Richard L, Nizou A, Cook-Moreau J et al (2012) Fingolimod potentiates the effects of sunitinib malate in a rat breast cancer model. Breast Cancer Res Treat 134(1):31–40

    Article  CAS  PubMed  Google Scholar 

  • Mullen TD, Hannun YA, Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J 441(3):789–802

    Article  CAS  PubMed  Google Scholar 

  • Nagahashi M, Tsuchida J, Moro K, Hasegawa M, Tatsuda K, Woelfel IA et al (2016a) High levels of sphingolipids in human breast cancer. J Surg Res 204(2):435–444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagahashi M, Yamada A, Miyazaki H, Allegood JC, Tsuchida J, Aoyagi T et al (2016b) Interstitial fluid sphingosine-1-phosphate in murine mammary gland and cancer and human breast tissue and cancer determined by novel methods. J Mammary Gland Biol Neoplasia 21(1):9–17

    Article  PubMed  PubMed Central  Google Scholar 

  • Nagahashi M, Yuza K, Hirose Y, Nakajima M, Ramanathan R, Hait NC et al (2016c) The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases. J Lipid Res 57(9):1636–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nemoto S, Nakamura M, Osawa Y, Kono S, Itoh Y, Okano Y et al (2009) Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation. J Biol Chem 284(16):10422–10432

    Article  PubMed  PubMed Central  Google Scholar 

  • Newton J, Lima S, Maceyka M, Spiegel S (2015) Revisiting the sphingolipid rheostat: evolving concepts in cancer therapy. Exp Cell Res 333(2):195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noack J, Choi J, Richter K, Kopp-Schneider A, Regnier-Vigouroux A (2014) A sphingosine kinase inhibitor combined with temozolomide induces glioblastoma cell death through accumulation of dihydrosphingosine and dihydroceramide, endoplasmic reticulum stress and autophagy. Cell Death Dis 5(9):e1425-e

    Article  Google Scholar 

  • Novgorodov SA, Szulc ZM, Luberto C, Jones JA, Bielawski J, Bielawska A et al (2005) Positively charged ceramide is a potent inducer of mitochondrial permeabilization. J Biol Chem 280(16):16096–16105

    Article  CAS  PubMed  Google Scholar 

  • Nunes J, Naymark M, Sauer L, Muhammad A, Keun H, Sturge J et al (2012) Circulating sphingosine-1-phosphate and erythrocyte sphingosine kinase-1 activity as novel biomarkers for early prostate cancer detection. Br J Cancer 106(5):909–915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogretmen B (2018) Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 18(1):33–50

    Article  CAS  PubMed  Google Scholar 

  • Ogretmen B, Hannun YA (2004) Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 4(8):604–616

    Article  CAS  PubMed  Google Scholar 

  • Ohotski J, Long J, Orange C, Elsberger B, Mallon E, Doughty J et al (2012) 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(8):1453–1459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohotski J, Rosen H, Bittman R, Pyne S, Pyne NJ (2014) 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(5):1040–1047

    Article  CAS  PubMed  Google Scholar 

  • Olgen S (2018) Overview on anticancer drug design and development. Curr Med Chem 25(15):1704–1719

    Article  CAS  PubMed  Google Scholar 

  • Oskouian B, Sooriyakumaran P, Borowsky AD, Crans A, Dillard-Telm L, Tam YY et al (2006) Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Proc Natl Acad Sci U S A 103(46):17384–17389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pal SK, Drabkin HA, Reeves JA, Hainsworth JD, Hazel SE, Paggiarino DA et al (2017) A phase 2 study of the sphingosine-1-phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma. Cancer 123(4):576–582

    Article  CAS  PubMed  Google Scholar 

  • Panneer Selvam S, De Palma RM, Oaks JJ, Oleinik N, Peterson YK, Stahelin RV et al (2015) Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation. Sci Signal 8(381):ra58-ra

    Article  Google Scholar 

  • Park S, Hatanpaa KJ, Xie Y, Mickey BE, Madden CJ, Raisanen JM et al (2009) The receptor interacting protein 1 inhibits p53 induction through NF-ÎşB activation and confers a worse prognosis in glioblastoma. Cancer Res 69(7):2809–2816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park W-J, Brenner O, Kogot-Levin A, Saada A, Merrill AH Jr, Pewzner-Jung Y et al (2015) Development of pheochromocytoma in ceramide synthase 2 null mice. Endocr Relat Cancer 22(4):623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Payne AW, Pant DK, Pan T-C, Chodosh LA (2014) Ceramide kinase promotes tumor cell survival and mammary tumor recurrence. Cancer Res 74(21):6352–6363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pchejetski D, Doumerc N, Golzio M, Naymark M, TeissiĂ© J, Kohama T et al (2008) Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models. Mol Cancer Ther 7(7):1836–1845

    Article  CAS  PubMed  Google Scholar 

  • Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ, Hannun YA (2000) Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem 275(12):9078–9084

    Article  CAS  PubMed  Google Scholar 

  • Pitman MR, Powell JA, Coolen C, Moretti PA, Zebol JR, Pham DH et al (2015) A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties. Oncotarget 6(9):7065

    Article  PubMed  PubMed Central  Google Scholar 

  • Powell JA, Lewis AC, Zhu W, Toubia J, Pitman MR, Wallington-Beddoe CT et al (2017) Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. Blood J Am Soc Hematol 129(6):771–782

    CAS  Google Scholar 

  • Pyne NJ, Pyne S (2010) Sphingosine 1-phosphate and cancer. Nat Rev Cancer 10(7):489–503

    Article  CAS  PubMed  Google Scholar 

  • Pyne NJ, Pyne S (2011) Selectivity and specificity of sphingosine 1-phosphate receptor ligands: “off-targets” or complex pharmacology? Front Pharmacol 2:26

    Article  PubMed  PubMed Central  Google Scholar 

  • Rahmaniyan M, Curley RW, Obeid LM, Hannun YA, Kraveka JM (2011) Identification of dihydroceramide desaturase as a direct in vitro target for fenretinide. J Biol Chem 286(28):24754–24764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rao RD, Cobleigh MA, Gray R, Graham ML 2nd, Norton L, Martino S et al (2011) Phase III double-blind, placebo-controlled, prospective randomized trial of adjuvant tamoxifen vs. tamoxifen and fenretinide in postmenopausal women with positive receptors (EB193): an intergroup trial coordinated by the Eastern Cooperative Oncology Group. Med Oncol 28(Suppl 1):S39–S47

    Article  PubMed  Google Scholar 

  • Ressom HW, Xiao JF, Tuli L, Varghese RS, Zhou B, Tsai T-H et al (2012) Utilization of metabolomics to identify serum biomarkers for hepatocellular carcinoma in patients with liver cirrhosis. Anal Chim Acta 743:90–100

    Article  CAS  PubMed  Google Scholar 

  • Revill K, Wang T, Lachenmayer A, Kojima K, Harrington A, Li J et al (2013) Genome-wide methylation analysis and epigenetic unmasking identify tumor suppressor genes in hepatocellular carcinoma. Gastroenterology 145(6):1424–1435. e25

    Article  CAS  PubMed  Google Scholar 

  • Reynolds CP, Maurer BJ, Kolesnick RN (2004) Ceramide synthesis and metabolism as a target for cancer therapy. Cancer Lett 206(2):169–180

    Article  CAS  PubMed  Google Scholar 

  • Reynolds GM, Visentin B, Sabbadini R (2017) Immunohistochemical detection of sphingosine-1-phosphate and sphingosine kinase-1 in human tissue samples and cell lines. In: Sphingosine-1-phosphate. Springer, pp 43–56

    Chapter  Google Scholar 

  • Riboni L, Abdel Hadi L, Navone SE, Guarnaccia L, Campanella R, Marfia G (2020) Sphingosine-1-phosphate in the tumor microenvironment: a signaling hub regulating cancer hallmarks. Cells 9(2):337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosa R, Marciano R, Malapelle U, Formisano L, Nappi L, D'Amato C et al (2013) Sphingosine kinase 1 overexpression contributes to cetuximab resistance in human colorectal cancer models. Clin Cancer Res 19(1):138–147

    Article  CAS  PubMed  Google Scholar 

  • Rosenfeldt MT, O’Prey J, Morton JP, Nixon C, MacKay G, Mrowinska A et al (2013) p53 status determines the role of autophagy in pancreatic tumour development. Nature 504(7479):296–300

    Article  CAS  PubMed  Google Scholar 

  • Rossi MJ, Sundararaj K, Koybasi S, Phillips MS, Szulc ZM, Bielawska A et al (2005) Inhibition of growth and telomerase activity by novel cationic ceramide analogs with high solubility in human head and neck squamous cell carcinoma cells. Otolaryngol Head Neck Surg 132(1):55–62

    Article  PubMed  Google Scholar 

  • Ryland LK, Doshi UA, Shanmugavelandy SS, Fox TE, Aliaga C, Broeg K et al (2013) C6-ceramide nanoliposomes target the Warburg effect in chronic lymphocytic leukemia. PLoS One 8(12):e84648

    Article  PubMed  PubMed Central  Google Scholar 

  • Samsel L, Zaidel G, Drumgoole HM, Jelovac D, Drachenberg C, Rhee JG et al (2004) The ceramide analog, B13, induces apoptosis in prostate cancer cell lines and inhibits tumor growth in prostate cancer xenografts. Prostate 58(4):382–393

    Article  CAS  PubMed  Google Scholar 

  • Sanmamed MF, Chen L (2018) A paradigm shift in cancer immunotherapy: from enhancement to normalization. Cell 175(2):313–326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Santana P, Peña LA, Haimovitz-Friedman A, Martin S, Green D, McLoughlin M et al (1996) Acid sphingomyelinase–deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 86(2):189–199

    Article  CAS  PubMed  Google Scholar 

  • Sasahira T, Akama Y, Fujii K, Kuniyasu H (2005) Expression of receptor for advanced glycation end products and HMGB1/amphoterin in colorectal adenomas. Virchows Arch 446(4):411–415

    Article  CAS  PubMed  Google Scholar 

  • Sato M, Ikeda H, Uranbileg B, Kurano M, Saigusa D, Aoki J et al (2016) Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human. Sci Rep 6(1):1–8

    Article  Google Scholar 

  • Savić R, Schuchman EH (2013) Use of acid sphingomyelinase for cancer therapy. Adv Cancer Res 117:91–115

    Article  PubMed  Google Scholar 

  • Schiffmann S, Sandner J, Birod K, Wobst I, Angioni C, Ruckhäberle E et al (2009a) Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 30(5):745–752

    Article  CAS  PubMed  Google Scholar 

  • Schiffmann S, Sandner J, Schmidt R, Birod K, Wobst I, Schmidt H et al (2009b) The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis. J Lipid Res 50(1):32–40

    Article  CAS  PubMed  Google Scholar 

  • Schubert KM, Scheid MP, Duronio V (2000) Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473. J Biol Chem 275(18):13330–13335

    Article  CAS  PubMed  Google Scholar 

  • Schulz G, Cheresh DA, Varki NM, Yu A, Staffileno LK, Reisfeld RA (1984) Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Res 44(12 Pt 1):5914–5920

    CAS  PubMed  Google Scholar 

  • Schwartz GK, Haimovitz-Friedman A, Dhupar SK, Ehleiter D, Maslak P, Lai L et al (1995) Potentiation of apoptosis by treatment with the protein kinase C-specific inhibitor safingol in mitomycin C-treated gastric cancer cells. J Natl Cancer Inst 87(18):1394–1399

    Article  CAS  PubMed  Google Scholar 

  • Schwartz GK, Ward D, Saltz L, Casper ES, Spiess T, Mullen E et al (1997) A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. Clin Cancer Res 3(4):537–543

    CAS  PubMed  Google Scholar 

  • Sedić M, GrbÄŤić P, Pavelić SK (2019) Bioactive sphingolipids as biomarkers predictive of disease severity and treatment response in cancer: current status and translational challenges. Anticancer Res 39(1):41–56

    Article  PubMed  Google Scholar 

  • Senkal CE, Ponnusamy S, Rossi MJ, Sundararaj K, Szulc Z, Bielawski J et al (2006) 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 Pharm Exp Ther 317(3):1188–1199

    Article  CAS  Google Scholar 

  • Separovic D, Shields AF, Philip PA, Bielawski J, Bielawska A, Pierce JS et al (2017) Altered levels of serum ceramide, sphingosine and sphingomyelin are associated with colorectal cancer: a retrospective pilot study. Anticancer Res 37(3):1213–1218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shamseddine A, Clarke C, Carroll B, Airola M, Mohammed S, Rella A et al (2015a) P53-dependent upregulation of neutral sphingomyelinase-2: role in doxorubicin-induced growth arrest. Cell Death Dis 6(10):e1947-e

    Article  Google Scholar 

  • Shamseddine AA, Airola MV, Hannun YA (2015b) Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes. Adv Biol Regul 57:24–41

    Article  CAS  PubMed  Google Scholar 

  • Shanbhogue P, Hannun YA (2018) Exploring the therapeutic landscape of sphingomyelinases. Lipid signaling in human diseases. Springer, pp 19–47

    Book  Google Scholar 

  • Sharma AK, Sk UH, Gimbor MA, Hengst JA, Wang X, Yun J et al (2010) Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs. Eur J Med Chem 45(9):4149–4156

    Article  CAS  PubMed  Google Scholar 

  • Shaw J, Costa-Pinheiro P, Patterson L, Drews K, Spiegel S, Kester M (2018) Novel sphingolipid-based cancer therapeutics in the personalized medicine era. Adv Cancer Res 140:327–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen Y, Zhao S, Wang S, Pan X, Zhang Y, Xu J et al (2019) S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma. EBioMedicine 40:210–223

    Article  PubMed  Google Scholar 

  • Shimizu H, Takahashi M, Kaneko T, Murakami T, Hakamata Y, Kudou S et al (2005) KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts. Circulation 111(2):222–229

    Article  CAS  PubMed  Google Scholar 

  • Shurin GV, Shurin MR, Bykovskaia S, Shogan J, Lotze MT, Barksdale EM Jr (2001) Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function. Cancer Res 61(1):363–369

    CAS  PubMed  Google Scholar 

  • Siskind LJ, Kolesnick RN, Colombini M (2006) Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion 6(3):118–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song L, Xiong H, Li J, Liao W, Wang L, Wu J et al (2011) Sphingosine kinase-1 enhances resistance to apoptosis through activation of PI3K/Akt/NF-ÎşB pathway in human non-small cell lung cancer. Clin Cancer Res 17(7):1839–1849

    Article  CAS  PubMed  Google Scholar 

  • Stolk DA, de Haas A, Vree J, Duinkerken S, LĂĽbbers J, van de Ven R et al (2020) Lipo-based vaccines as an approach to target dendritic cells for induction of T- and iNKT cell responses. Front Immunol 11:990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stover T, Kester M (2003) Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells. J Pharmacol Exp Ther 307(2):468–475

    Article  CAS  PubMed  Google Scholar 

  • Strader CR, Pearce CJ, Oberlies NH (2011) Fingolimod (FTY720): a recently approved multiple sclerosis drug based on a fungal secondary metabolite. J Nat Prod 74(4):900–907

    Article  CAS  PubMed  Google Scholar 

  • Strilic B, Yang L, Albarrán-Juárez J, Wachsmuth L, Han K, MĂĽller UC et al (2016) Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536(7615):215–218

    Article  CAS  PubMed  Google Scholar 

  • Strub GM, Paillard M, Liang J, Gomez L, Allegood JC, Hait NC et al (2011) Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. FASEB J 25(2):600–612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Struckhoff AP, Bittman R, Burow ME, Clejan S, Elliott S, Hammond T et al (2004) Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J Pharmacol Exp Ther 309(2):523–532

    Article  CAS  PubMed  Google Scholar 

  • Sugiura M, Kono K, Liu H, Shimizugawa T, Minekura H, Spiegel S et al (2002) Ceramide kinase, a novel lipid kinase: molecular cloning and functional characterization. J Biol Chem 277(26):23294–23300

    Article  CAS  PubMed  Google Scholar 

  • Sukocheva O, Wang L, Verrier E, Vadas MA, Xia P (2009) Restoring endocrine response in breast cancer cells by inhibition of the sphingosine kinase-1 signaling pathway. Endocrinology 150(10):4484–4492

    Article  CAS  PubMed  Google Scholar 

  • Sumitomo M, Ohba M, Asakuma J, Asano T, Kuroki T, Asano T et al (2002) Protein kinase Cδ amplifies ceramide formation via mitochondrial signaling in prostate cancer cells. J Clin Investig 109(6):827–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tallima H, Azzazy HM, El Ridi R (2021) Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion. Lipids Health Dis 20(1):1–12

    Article  Google Scholar 

  • Tani M, Hannun YA (2007) Neutral sphingomyelinase 2 is palmitoylated on multiple cysteine residues: role of palmitoylation in subcellular localization. J Biol Chem 282(13):10047–10056

    Article  CAS  PubMed  Google Scholar 

  • Taniguchi M, Kitatani K, Kondo T, Hashimoto-Nishimura M, Asano S, Hayashi A et al (2012) Regulation of autophagy and its associated cell death by “sphingolipid rheostat”: reciprocal role of ceramide and sphingosine 1-phosphate in the mammalian target of rapamycin pathway. J Biol Chem 287(47):39898–39910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thon L, Möhlig H, Mathieu S, Lange A, Bulanova E, Winoto-Morbach S et al (2005) Ceramide mediates caspase-independent programmed cell death. FASEB J 19(14):1945–1956

    Article  CAS  PubMed  Google Scholar 

  • Tsao CY, Sabbatino F, Cheung NK, Hsu JC, Villani V, Wang X et al (2015) Anti-proliferative and pro-apoptotic activity of GD2 ganglioside-specific monoclonal antibody 3F8 in human melanoma cells. Oncoimmunology 4(8):e1023975

    Article  PubMed  PubMed Central  Google Scholar 

  • Tseng T-H, Shen C-H, Huang W-S, Chen C-N, Liang W-H, Lin T-H et al (2014) Activation of neutral-sphingomyelinase, MAPKs, and p75 NTR-mediating caffeic acid phenethyl ester–induced apoptosis in C6 glioma cells. J Biomed Sci 21(1):1–11

    Article  Google Scholar 

  • Tsuchida T, Saxton RE, Morton DL, Irie RF (1987) Gangliosides of human melanoma. J Natl Cancer Inst 78(1):45–54

    Article  CAS  PubMed  Google Scholar 

  • Tsukamoto S, Huang Y, Kumazoe M, Lesnick C, Yamada S, Ueda N et al (2015) Sphingosine kinase-1 protects multiple myeloma from apoptosis driven by cancer-specific inhibition of RTKs. Mol Cancer Ther 14(10):2303–2312

    Article  CAS  PubMed  Google Scholar 

  • Ubai T, Azuma H, Kotake Y, Inamoto T, Takahara K, Ito Y et al (2007) FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft. Anticancer Res 27(1A):75–88

    CAS  PubMed  Google Scholar 

  • Vaishampayan U, Heilbrun LK, Parchment RE, Jain V, Zwiebel J, Boinpally RR et al (2005) Phase II trial of fenretinide in advanced renal carcinoma. Investig New Drugs 23(2):179–185

    Article  CAS  Google Scholar 

  • van der Weyden L, Arends MJ, Campbell AD, Bald T, Wardle-Jones H, Griggs N et al (2017) Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature 541(7636):233–236

    Article  PubMed  PubMed Central  Google Scholar 

  • van Vlerken LE, Duan Z, Seiden MV, Amiji MM (2007) Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res 67(10):4843–4850

    Article  PubMed  Google Scholar 

  • Vandenabeele P, Galluzzi L, Berghe TV, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10):700–714

    Article  CAS  PubMed  Google Scholar 

  • Veldman RJ, Zerp S, van Blitterswijk WJ, Verheij M (2004) N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx. Br J Cancer 90(4):917–925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venant H, Rahmaniyan M, Jones EE, Lu P, Lilly MB, Garrett-Mayer E et al (2015) 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(12):2744–2752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Veronesi U, Mariani L, Decensi A, Formelli F, Camerini T, Miceli R et al (2006) Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Ann Oncol 17(7):1065–1071

    Article  CAS  PubMed  Google Scholar 

  • Visentin B, Vekich JA, Sibbald BJ, Cavalli AL, Moreno KM, Matteo RG et al (2006) 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(3):225–238

    Article  CAS  PubMed  Google Scholar 

  • Wang Q, Chen W, Xu X, Li B, He W, Padilla MT et al (2013a) RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species. Carcinogenesis 34(9):2119–2128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Z, Min X, Xiao S-H, Johnstone S, Romanow W, Meininger D et al (2013b) Molecular basis of sphingosine kinase 1 substrate recognition and catalysis. Structure 21(5):798–809

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Liang Y, Chang W, Hu B, Zhang Y (2018) Triple negative breast cancer depends on sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/sphingosine 1-phosphate receptor 3 (S1PR3)/notch signaling for metastasis. Med Sci Monit 24:1912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Ding Y, Wang C, Gao M, Xu Y, Ma X et al (2020) Fenretinide-polyethylene glycol (PEG) conjugate with improved solubility enhanced cytotoxicity to cancer cell and potent in vivo efficacy. Pharm Dev Technol 25(8):962–970

    Article  CAS  PubMed  Google Scholar 

  • Watters RJ, Wang H-G, Sung S-S, Loughran PT, Liu X (2011) Targeting sphingosine-1-phosphate receptors in cancer. Anti Cancer Agents Med Chem 11(9):810–817

    Article  CAS  Google Scholar 

  • Weiss HL, Urban DA, Grizzle WE, Cronin KA, Freedman LS, Kelloff GJ et al (2001) Bayesian monitoring of a phase 2 chemoprevention trial in high-risk cohorts for prostate cancer. Urology 57(4 Suppl 1):220–223

    Article  CAS  PubMed  Google Scholar 

  • Wenderfer SE, Stepkowski SM, Braun MC (2008) Increased survival and reduced renal injury in MRL/lpr mice treated with a novel sphingosine-1-phosphate receptor agonist. Kidney Int 74(10):1319–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • White C, Alshaker H, Cooper C, Winkler M, Pchejetski D (2016) The emerging role of FTY720 (Fingolimod) in cancer treatment. Oncotarget 7(17):23106

    Article  PubMed  PubMed Central  Google Scholar 

  • White-Gilbertson S, Mullen T, Senkal C, Lu P, Ogretmen B, Obeid L et al (2009) Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells. Oncogene 28(8):1132–1141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wijesinghe DS, Lamour NF, Gomez-Munoz A, Chalfant CE (2007) Ceramide kinase and ceramide-1-phosphate. Methods Enzymol 434:265–292

    Article  CAS  PubMed  Google Scholar 

  • Wu ZL, Schwartz E, Seeger R, Ladisch S (1986) Expression of GD2 ganglioside by untreated primary human neuroblastomas. Cancer Res 46(1):440–443

    CAS  PubMed  Google Scholar 

  • Wu D, Xing GW, Poles MA, Horowitz A, Kinjo Y, Sullivan B et al (2005) Bacterial glycolipids and analogs as antigens for CD1d-restricted NKT cells. Proc Natl Acad Sci U S A 102(5):1351–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xing Y, Wang ZH, Ma DH, Han Y (2014) FTY720 enhances chemosensitivity of colon cancer cells to doxorubicin and etoposide via the modulation of P-glycoprotein and multidrug resistance protein 1. J Dig Dis 15(5):246–259

    Article  CAS  PubMed  Google Scholar 

  • Yamada A, Nagahashi M, Aoyagi T, Huang W-C, Lima S, Hait NC et al (2018) ABCC1-exported sphingosine-1-phosphate, produced by sphingosine kinase 1, shortens survival of mice and patients with breast cancer. Mol Cancer Res 16(6):1059–1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young N, Van Brocklyn JR (2007) Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness. Exp Cell Res 313(8):1615–1627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young MR, Neville BW, Chi AC, Lathers DM, Gillespie MB, Day TA (2007) Autocrine motility-stimulatory pathways of oral premalignant lesion cells. Clin Exp Metastasis 24(2):131–139

    Article  CAS  PubMed  Google Scholar 

  • Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E et al (2006) Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci 103(13):4952–4957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zamora-Pineda J, Kumar A, Suh JH, Zhang M, Saba JD (2016) Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress. J Exp Med 213(12):2773–2791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang P, Fu C, Hu Y, Dong C, Song Y, Song E (2015a) C 6-ceramide nanoliposome suppresses tumor metastasis by eliciting PI3K and PKCζ tumor-suppressive activities and regulating integrin affinity modulation. Sci Rep 5(1):1–16

    Google Scholar 

  • Zhang Z, Yan Z, Yuan Z, Sun Y, He H, Mai C (2015b) SPHK1 inhibitor suppresses cell proliferation and invasion associated with the inhibition of NF-ÎşB pathway in hepatocellular carcinoma. Tumour Biol 36(3):1503–1509

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Kitatani K, Toyoshima M, Ishibashi M, Usui T, Minato J et al (2018) Ceramide nanoliposomes as a MLKL-dependent, necroptosis-inducing, chemotherapeutic reagent in ovarian cancer. Mol Cancer Ther 17(1):50–59

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y-h, Cui S-x, Wan S-b, Wu S-h, Qu X-j (2021) Increased S1P induces S1PR2 internalization to blunt the sensitivity of colorectal cancer to 5-fluorouracil via promoting intracellular uracil generation. Acta Pharmacol Sin 42(3):460–469

    Article  CAS  PubMed  Google Scholar 

  • Zhao J, Liu J, Lee J-F, Zhang W, Kandouz M, VanHecke GC et al (2016) 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(53):27343–27353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng W, Kollmeyer J, Symolon H, Momin A, Munter E, Wang E et al (2006) Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochimica et Biophysica Acta (BBA)-Biomembranes 1758(12):1864–1884

    Article  CAS  PubMed  Google Scholar 

  • Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y et al (2004) Lysosomal glycosphingolipid recognition by NKT cells. Science 306(5702):1786–1789

    Article  CAS  PubMed  Google Scholar 

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  1. Authors Mohamad Bahij Moumneh and Tarek Bou Dargham have equally contributed to this chapter.

Authors and Affiliations

  1. Faculty of Medicine, University of Balamand, Koura, Lebanon

    Mohamad Bahij Moumneh & Tarek Bou Dargham

  2. Faculty of Medicine, Department of Pediatrics and Adolescent Medicine, Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon

    Marguerite Mrad & Ghassan Dbaibo

  3. Faculty of Medicine, Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon

    Marguerite Mrad & Ghassan Dbaibo

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  1. Mohamad Bahij Moumneh
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  2. Tarek Bou Dargham
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  3. Marguerite Mrad
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  4. Ghassan Dbaibo
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Correspondence to Ghassan Dbaibo .

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  1. Division of Clinical Immunology, Karolinska University Hospital, Huddinge, Sweden

    Nima Rezaei

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Moumneh, M.B., Bou Dargham, T., Mrad, M., Dbaibo, G. (2023). Sphingolipid Metabolism in Cancer: Potential Therapeutic Target. In: Rezaei, N. (eds) Handbook of Cancer and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-80962-1_264-1

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