References

1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 2020, 70, 7–30.
2. Ward, E.M.; Sherman, R.L.; Henley, S.J.; Jemal, A.; Siegel, D.A.; Feuer, E.J.; Firth, A.U.; Kohler, B.A.; Scott, S.; Ma, J.; et al. Annual report to the nation on the status of cancer, featuring cancer in men and women age 20–49 years. JNCI J. Natl. Cancer Inst. 2019, 111, 1279–1297.
3. Thrift, A.P.; Gudenkauf, F.J. Melanoma incidence among non-Hispanic whites in all 50 US states from 2001 through 2015. JNCI J. Natl. Cancer Inst. 2020, 112, 533–539.
4. Young, M.M.; Kester, M.; Wang, H.-G. Sphingolipids: Regulators of crosstalk between apoptosis and autophagy. J. Lipid Res. 2013, 54, 5–19.
5. Jiang, W.; Ogretmen, B. Autophagy paradox and ceramide. Biochim. Biophys. Acta 2014, 1841, 783–792.
6. Sentelle, R.D.; Senkal, C.E.; Jiang, W.; Ponnusamy, S.; Gencer, S.; Selvam, S.P.; Ramshesh, V.K.; Peterson, Y.K.; Lemasters, J.J.; Szulc, Z.M.; et al. Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat. Chem. Biol. 2012, 8, 831–838.
7. Ogretmen, B.; Hannun, Y.A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat. Rev. Cancer 2004, 4, 604–616.
8. Saddoughi, S.A.; Ogretmen, B. Diverse functions of ceramide in cancer cell death and proliferation. Adv. Cancer Res. 2013, 117, 37–58.
9. Hannun, Y.A.; Obeid, L.M. Principles of bioactive lipid signalling: Lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 2008, 9, 139–150.
10. Ogretmen, B. Sphingolipid metabolism in cancer signalling and therapy. Nat. Rev. Cancer 2018, 18, 33–50.
11. Hanada, K.; Kumagai, K.; Yasuda, S.; Miura, Y.; Kawano, M.; Fukasawa, M.; Nishijima, M. Molecular machinery for non-vesicular trafficking of ceramide. Nature 2003, 426, 803–809.
12. Laviad, E.L.; Kelly, S.; Merrill, A.H.; Futerman, A.H. Modulation of ceramide synthase activity via dimerization. J. Biol. Chem. 2012, 287, 21025–21033.
13. Futerman, A.H.; Hannun, Y.A. The complex life of simple sphingolipids. EMBO Rep. 2004, 5, 777–782.
14. Kumagai, K.; Yasuda, S.; Okemoto, K.; Nishijima, M.; Kobayashi, S.; Hanada, K. CERT mediates intermembrane transfer of various molecular species of ceramides. J. Biol. Chem. 2005, 280, 6488–6495.
15. Davis, D.L.; Gable, K.; Suemitsu, J.; Dunn, T.M.; Wattenberg, B.W. The ORMDL/Orm–serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes. J. Biol. Chem. 2019, 294, 13.
16. Cai, L.; Oyeniran, C.; Biswas, D.D.; Allegood, J.; Milstien, S.; Kordula, T.; Maceyka, M.; Spiegel, S. ORMDL proteins regulate ceramide levels during sterile inflammation. J. Lipid Res. 2016, 57, 1412–1422.
17. Vacaru, A.M.; Tafesse, F.G.; Ternes, P.; Kondylis, V.; Hermansson, M.; Brouwers, J.F.H.M.; Somerharju, P.; Rabouille, C.; Holthuis, J.C.M. Sphingomyelin synthase-related protein smsr controls ceramide homeostasis in the er. J. Cell Biol. 2009, 185, 1013–1027.
18. Pewzner-Jung, Y.; Ben-Dor, S.; Futerman, A.H. When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: Insights into the regulation of ceramide synthesis. J. Biol. Chem. 2006, 281, 25001–25005.
19. Kraveka, J.M.; Li, L.; Szulc, Z.M.; Bielawski, J.; Ogretmen, B.; Hannun, Y.A.; Obeid, L.M.; Bielawska, A. Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J. Biol. Chem. 2007, 282, 16718–16728.
20. Jennemann, R.; Rabionet, M.; Gorgas, K.; Epstein, S.; Dalpke, A.; Rothermel, U.; Bayerle, A.; van der Hoeven, F.; Imgrund, S.; Kirsch, J.; et al. Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum. Mol. Genet. 2012, 21, 586–608.
21. Ogretmen, B.; Pettus, B.J.; Rossi, M.J.; Wood, R.; Usta, J.; Szulc, Z.; Bielawska, A.; Obeid, L.M.; Hannun, Y.A. 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. 2002, 277, 12960–12969.
22. Saddoughi, S.A.; Song, P.; Ogretmen, B. Roles of bioactive sphingolipids in cancer biology and therapeutics. Subcell. Biochem. 2008, 49, 413–440.
23. Maceyka, M.; Spiegel, S. Sphingolipid metabolites in inflammatory disease. Nature 2014, 510, 58–67.
24. Huang, W.-C.; Liang, J.; Nagahashi, M.; Avni, D.; Yamada, A.; Maceyka, M.; Wolen, A.R.; Kordula, T.; Milstien, S.; Takabe, K.; et al. Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2016, 30, 2945–2958.
25. Selvam, S.P.; Ogretmen, B. Sphingosine kinase/sphingosine 1-phosphate signaling in cancer therapeutics and drug resistance. Handb. Exp. Pharmacol. 2013, 216, 3–27.
26. D’Angelo, G.; Uemura, T.; Chuang, C.-C.; Polishchuk, E.; Santoro, M.; Ohvo-Rekilä, H.; Sato, T.; Di Tullio, G.; Varriale, A.; D’Auria, S.; et al. Vesicular and non-vesicular transport feed distinct glycosylation pathways in the golgi. Nature 2013, 501, 116–120.
27. Senkal, C.E.; Salama, M.F.; Snider, A.J.; Allopenna, J.J.; Rana, N.A.; Koller, A.; Hannun, Y.A.; Obeid, L.M. Ceramide is metabolized to acylceramide and stored in lipid droplets. Cell Metab. 2017, 25, 686–697.
28. Arana, L.; Gangoiti, P.; Ouro, A.; Trueba, M.; Gómez-Muñoz, A. Ceramide and ceramide 1-phosphate in health and disease. Lipids Health Dis. 2010, 9, 15.
29. Huitema, K.; van den Dikkenberg, J.; Brouwers, J.F.H.M.; Holthuis, J.C.M. Identification of a family of animal sphingomyelin synthases. EMBO J. 2004, 23, 33–44.
30. Helke, K.; Angel, P.; Lu, P.; Garrett-Mayer, E.; Ogretmen, B.; Drake, R.; Voelkel-Johnson, C. Ceramide synthase 6 deficiency enhances inflammation in the dss model of colitis. Sci. Rep. 2018, 8, 1627.
31. Zhang, Y.; Wang, Y.; Wan, Z.; Liu, S.; Cao, Y.; Zeng, Z. Sphingosine kinase 1 and cancer: A systematic review and meta-analysis. PLoS ONE 2014, 9, e90362.
32. Xu, Y.; Dong, B.; Wang, J.; Zhang, J.; Xue, W.; Huang, Y. Sphingosine kinase 1 overexpression contributes to sunitinib resistance in clear cell renal cell carcinoma. Oncoimmunology 2018, 7, e1502130.
33. Abuhusain, H.J.; Matin, A.; Qiao, Q.; Shen, H.; Kain, N.; Day, B.W.; Stringer, B.W.; Daniels, B.; Laaksonen, M.A.; Teo, C.; et al. A metabolic shift favoring sphingosine 1-phosphate at the expense of ceramide controls glioblastoma angiogenesis. J. Biol. Chem. 2013, 288, 37355–37364.
34. Xia, P.; Gamble, J.R.; Wang, L.; Pitson, S.M.; Moretti, P.A.; Wattenberg, B.W.; D’Andrea, R.J.; Vadas, M.A. An oncogenic role of sphingosine kinase. Curr. Biol. CB 2000, 10, 1527–1530.
35. Wang, X.; Sun, Y.; Peng, X.; Naqvi, S.M.A.S.; Yang, Y.; Zhang, J.; Chen, M.; Chen, Y.; Chen, H.; Yan, H.; et al. The tumorigenic effect of sphingosine kinase 1 and its potential therapeutic target. Cancer Control 2020, 27, 107327482097666.
36. Kawamori, T.; Kaneshiro, T.; Okumura, M.; Maalouf, S.; Uflacker, A.; Bielawski, J.; Hannun, Y.A.; Obeid, L.M. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2009, 23, 405–414.
37. Acharya, S.; Yao, J.; Li, P.; Zhang, C.; Lowery, F.J.; Zhang, Q.; Guo, H.; Qu, J.; Yang, F.; Wistuba, I.I.; et al. Sphingosine kinase 1 signaling promotes metastasis of triple-negative breast cancer. Cancer Res. 2019, 79, 4211–4226.
38. Wang, S.; Liang, Y.; Chang, W.; Hu, B.; Zhang, Y. 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. 2018, 24, 1912–1923.
39. Pyne, N.J.; Pyne, S. Recent advances in the role of sphingosine 1-phosphate in cancer. FEBS Lett. 2020, 594, 3583–3601.
40. Hart, P.C.; Chiyoda, T.; Liu, X.; Weigert, M.; Curtis, M.; Chiang, C.-Y.; Loth, R.; Lastra, R.; McGregor, S.M.; Locasale, J.W.; et al. SPHK1 is a novel target of metformin in ovarian cancer. Mol. Cancer Res. MCR 2019, 17, 870–881.
41. Lee, J.-W.; Ryu, J.-Y.; Yoon, G.; Jeon, H.-K.; Cho, Y.-J.; Choi, J.-J.; Song, S.Y.; Do, I.-G.; Lee, Y.-Y.; Kim, T.-J.; et al. Sphingosine kinase 1 as a potential therapeutic target in epithelial ovarian cancer. Int. J. Cancer 2015, 137, 221–229.
42. Salama, M.F.; Carroll, B.; Adada, M.; Pulkoski-Gross, M.; Hannun, Y.A.; Obeid, L.M. A novel role of sphingosine kinase-1 in the invasion and angiogenesis of VHL mutant clear cell renal cell carcinoma. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2015, 29, 2803–2813.
43. Dai, L.; Liu, Y.; Xie, L.; Wu, X.; Qiu, L.; Di, W. Sphingosine kinase 1/sphingosine-1-phosphate (S1P)/S1P receptor axis is involved in ovarian cancer angiogenesis. Oncotarget 2017, 8, 74947–74961.
44. Kim, H.-S.; Yoon, G.; Ryu, J.-Y.; Cho, Y.-J.; Choi, J.-J.; Lee, Y.-Y.; Kim, T.-J.; Choi, C.-H.; Song, S.Y.; Kim, B.-G.; et al. Sphingosine kinase 1 is a reliable prognostic factor and a novel therapeutic target for uterine cervical cancer. Oncotarget 2015, 6, 26746–26756.
45. Cohen, J.A.; Barkhof, F.; Comi, G.; Hartung, H.-P.; Khatri, B.O.; Montalban, X.; Pelletier, J.; Capra, R.; Gallo, P.; Izquierdo, G.; et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362, 402–415.
46. Kappos, L.; Radue, E.-W.; O’Connor, P.; Polman, C.; Hohlfeld, R.; Calabresi, P.; Selmaj, K.; Agoropoulou, C.; Leyk, M.; Zhang-Auberson, L.; et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362, 387–401.
47. Saddoughi, S.A.; Gencer, S.; Peterson, Y.K.; Ward, K.E.; Mukhopadhyay, A.; Oaks, J.; Bielawski, J.; Szulc, Z.M.; Thomas, R.J.; Selvam, S.P.; et al. Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol. Med. 2013, 5, 105–121.
48. Liang, J.; Nagahashi, M.; Kim, E.Y.; Harikumar, K.B.; Yamada, A.; Huang, W.-C.; Hait, N.C.; Allegood, J.C.; Price, M.M.; Avni, D.; et al. Sphingosine-1-phosphate links persistent stat3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell 2013, 23, 107–120.
49. Neviani, P.; Harb, J.G.; Oaks, J.J.; Santhanam, R.; Walker, C.J.; Ellis, J.J.; Ferenchak, G.; Dorrance, A.M.; Paisie, C.A.; Eiring, A.M.; et al. PP2A-activating drugs selectively eradicate TK1-resistant chronic myeloid leukemic stem cells. J. Clin. Investig. 2013, 123, 4144–4157.
50. Young, M.M.; Takahashi, Y.; Fox, T.E.; Yun, J.K.; Kester, M.; Wang, H.-G. Sphingosine Kinase 1 Cooperates with Autophagy to Maintain Endocytic Membrane Trafficking. Cell Rep. 2016, 17, 1532–1545.
51. Davis, D.; Kannan, M.; Wattenberg, B. Orm/ORMDL proteins: Gate guardians and master regulators. Adv. Biol. Regul. 2018, 70.
52. Panneer Selvam, S.; De Palma, R.M.; Oaks, J.J.; Oleinik, N.; Peterson, Y.K.; Stahelin, R.V.; Skordalakes, E.; Ponnusamy, S.; Garrett-Mayer, E.; Smith, C.D.; et al. Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation. Sci. Signal. 2015, 8, ra58.
53. Lewis, C.S.; Voelkel-Johnson, C.; Smith, C.D. Suppression of c-Myc and RRM2 expression in pancreatic cancer cells by the sphingosine kinase-2 inhibitor ABC294640. Oncotarget 2016, 7, 60181–60192.
54. Britten, C.D.; Garrett-Mayer, E.; Chin, S.H.; Shirai, K.; Ogretmen, B.; Bentz, T.A.; Brisendine, A.; Anderton, K.; Cusack, S.L.; Maines, L.W.; 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. 2017, 23, 4642–4650.
55. Venkata, J.K.; An, N.; Stuart, R.; Costa, L.J.; Cai, H.; Coker, W.; Song, J.H.; Gibbs, K.; Matson, T.; Garrett-Mayer, E.; et al. Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood 2014, 124, 1915–1925.
56. Qin, Z.; Dai, L.; Trillo-Tinoco, J.; Senkal, C.; Wang, W.; Reske, T.; Bonstaff, K.; Del Valle, L.; Rodriguez, P.; Flemington, E.; et al. Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma. Mol. Cancer Ther. 2014, 13, 154–164.
57. Wang, Q.; Li, J.; Li, G.; Li, Y.; Xu, C.; Li, M.; Xu, G.; Fu, S. Prognostic significance of sphingosine kinase 2 expression in non-small cell lung cancer. Tumour Biol. J. Int. Soc. Oncodev. Biol. Med. 2014, 35, 363–368.
58. Zhang, L.; Liu, X.; Zuo, Z.; Hao, C.; Ma, Y. Sphingosine kinase 2 promotes colorectal cancer cell proliferation and invasion by enhancing MYC expression. Tumour Biol. J. Int. Soc. Oncodev. Biol. Med. 2016, 37, 8455–8460.
59. Hait, N.C.; Bellamy, A.; Milstien, S.; Kordula, T.; Spiegel, S. Sphingosine kinase type 2 activation by ERK-mediated phosphorylation. J. Biol. Chem. 2007, 282, 12058–12065.
60. Senkal, C.E.; Ponnusamy, S.; Rossi, M.J.; Bialewski, J.; Sinha, D.; Jiang, J.C.; Jazwinski, S.M.; Hannun, Y.A.; Ogretmen, B. 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. 2007, 6, 712–722.
61. Karahatay, S.; Thomas, K.; Koybasi, S.; Senkal, C.E.; Elojeimy, S.; Liu, X.; Bielawski, J.; Day, T.A.; Gillespie, M.B.; Sinha, D.; et al. Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): Attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis. Cancer Lett. 2007, 256, 101–111.
62. Koybasi, S.; Senkal, C.E.; Sundararaj, K.; Spassieva, S.; Bielawski, J.; Osta, W.; Day, T.A.; Jiang, J.C.; Jazwinski, S.M.; Hannun, Y.A.; 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. 2004, 279, 44311–44319.
63. Saddoughi, S.A.; Garrett-Mayer, E.; Chaudhary, U.; O’Brien, P.E.; Afrin, L.B.; Day, T.A.; Gillespie, M.B.; Sharma, A.K.; Wilhoit, C.S.; Bostick, R.; 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. Off. J. Am. Assoc. Cancer Res. 2011, 17, 6097–6105.
64. Brachtendorf, S.; El-Hindi, K.; Grösch, S. Ceramide synthases in cancer therapy and chemoresistance. Prog. Lipid Res. 2019, 74, 160–185.
65. Meyers-Needham, M.; Ponnusamy, S.; Gencer, S.; Jiang, W.; Thomas, R.J.; Senkal, C.E.; Ogretmen, B. Concerted functions of HDAC1 and microRNA-574-5p repress alternatively spliced ceramide synthase 1 expression in human cancer cells. EMBO Mol. Med. 2012, 4, 78–92.
66. Thomas, R.J.; Oleinik, N.; Panneer Selvam, S.; Vaena, S.G.; Dany, M.; Nganga, R.N.; Depalma, R.; Baron, K.D.; Kim, J.; Szulc, Z.M.; et al. HPV/E7 induces chemotherapy-mediated tumor suppression by ceramide-dependent mitophagy. EMBO Mol. Med. 2017, 9, 1030–1051.
67. Chalfant, C.E.; Kishikawa, K.; Mumby, M.C.; Kamibayashi, C.; Bielawska, A.; Hannun, Y.A. Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid. J. Biol. Chem. 1999, 274, 20313–20317.
68. Yeh, E.; Cunningham, M.; Arnold, H.; Chasse, D.; Monteith, T.; Ivaldi, G.; Hahn, W.C.; Stukenberg, P.T.; Shenolikar, S.; Uchida, T.; et al. A signalling pathway controlling c-MYC degradation that impacts oncogenic transformation of human cells. Nat. Cell Biol. 2004, 6, 308–318.
69. .Salas, A.; Ponnusamy, S.; Senkal, C.E.; Meyers-Needham, M.; Selvam, S.P.; Saddoughi, S.A.; Apohan, E.; Sentelle, R.D.; Smith, C.; Gault, C.R.; 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 2011, 117, 5941–5952.
70. Mukhopadhyay, A.; Saddoughi, S.A.; Song, P.; Sultan, I.; Ponnusamy, S.; Senkal, C.E.; Snook, C.F.; Arnold, H.K.; Sears, R.C.; Hannun, Y.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. Off. Publ. Fed. Am. Soc. Exp. Biol. 2009, 23, 751–763.
71. De Palma, R.M.; Parnham, S.R.; Li, Y.; Oaks, J.J.; Peterson, Y.K.; Szulc, Z.M.; Roth, B.M.; Xing, Y.; Ogretmen, B. The NMR-based characterization of the FTY720-set complex reveals an alternative mechanism for the attenuation of the inhibitory SET-PP2A interaction. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2019, 33, 7647–7666.
72. Vanni, N.; Fruscione, F.; Ferlazzo, E.; Striano, P.; Robbiano, A.; Traverso, M.; Sander, T.; Falace, A.; Gazzerro, E.; Bramanti, P.; et al. Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy: CERS1 deficiency in novel PME. Ann. Neurol. 2014, 76, 206–212.
73. Chen, L.; Chen, H.; Li, Y.; Li, L.; Qiu, Y.; Ren, J. Endocannabinoid and ceramide levels are altered in patients with colorectal cancer. Oncol. Rep. 2015, 34, 447–454.
74. Wang, Z.; Wen, L.; Zhu, F.; Wang, Y.; Xie, Q.; Chen, Z.; Li, Y. Overexpression of ceramide synthase 1 increases C18-ceramide and leads to lethal autophagy in human glioma. Oncotarget 2017, 8, 104022–104036.
75. Gencer, S.; Oleinik, N.; Kim, J.; Panneer Selvam, S.; De Palma, R.; Dany, M.; Nganga, R.; Thomas, R.J.; Senkal, C.E.; Howe, P.H.; et al. TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis. Sci. Signal. 2017, 10, eaam7464.
76. Imgrund, S.; Hartmann, D.; Farwanah, H.; Eckhardt, M.; Sandhoff, R.; Degen, J.; Gieselmann, V.; Sandhoff, K.; Willecke, K. Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J. Biol. Chem. 2009, 284, 33549–33560.
77. Pewzner-Jung, Y.; Park, H.; Laviad, E.L.; Silva, L.C.; Lahiri, S.; Stiban, J.; Erez-Roman, R.; Brügger, B.; Sachsenheimer, T.; Wieland, F.; et al. A critical role for ceramide synthase 2 in liver homeostasis. J. Biol. Chem. 2010, 285, 10902–10910.
78. Bickert, A.; Kern, P.; van Uelft, M.; Herresthal, S.; Ulas, T.; Gutbrod, K.; Breiden, B.; Degen, J.; Sandhoff, K.; Schultze, J.L.; et al. Inactivation of ceramide synthase 2 catalytic activity in mice affects transcription of genes involved in lipid metabolism and cell division. Biochim. Biophys. Acta BBA-Mol. Cell Biol. Lipids 2018, 1863, 734–749.
79. Fan, S.; Wang, Y.; Lu, J.; Zheng, Y.; Wu, D.; Zhang, Z.; Shan, Q.; Hu, B.; Li, M.; Cheng, W. CERS2 suppresses tumor cell invasion and is associated with decreased V-ATPase and MMP-2/MMP-9 activities in breast cancer: CERS2 suppresses breast cancer invasion. J. Cell. Biochem. 2015, 116, 502–513.
80. Jang, S.; Park, W.; Min, H.; Kwon, T.; Baek, S.; Hwang, I.; Kim, S.; Park, J. Altered MMA expression levels of the major components of sphingolipid metabolism, ceramide synthases and their clinical implication in colorectal cancer. Oncol. Rep. 2018.
81. Kijanka, G.; Hector, S.; Kay, E.W.; Murray, F.; Cummins, R.; Murphy, D.; MacCraith, B.D.; Prehn, J.H.M.; Kenny, D. Human IgG antibody profiles differentiate between symptomatic patients with and without colorectal cancer. Gut 2010, 59, 69–78.
82. El-Hindi, K.; Brachtendorf, S.; Hartel, J.C.; Oertel, S.; Birod, K.; Trautmann, S.; Thomas, D.; Ulshöfer, T.; Weigert, A.; Utermöhlen, O.; et al. Ceramide synthase 5 deficiency aggravates dextran sodium sulfate-induced colitis and colon carcinogenesis and impairs T-cell activation. Cancers 2020, 12, 1753.
83. Won, J.-S.; Singh, I. Sphingolipid signaling and redox regulation. Free Radic. Biol. Med. 2006, 40.
84. Fekry, B.; Jeffries, K.A.; Esmaeilniakooshkghazi, A.; Ogretmen, B.; Krupenko, S.A.; Krupenko, N.I. CerS6 Is a Novel Transcriptional Target of p53 Protein Activated by Non-genotoxic Stress. J. Biol. Chem. 2016, 291, 16586–16596.
85. White-Gilbertson, S.; Mullen, T.; Senkal, C.; Lu, P.; Ogretmen, B.; Obeid, L.; Voelkel-Johnson, C. Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells. Oncogene 2009, 28, 1132–1141.
86. Lee, H.; Rotolo, J.A.; Mesicek, J.; Penate-Medina, T.; Rimner, A.; Liao, W.-C.; Yin, X.; Ragupathi, G.; Ehleiter, D.; Gulbins, E.; et al. Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS ONE 2011, 6, e19783.
87. Senkal, C.E.; Ponnusamy, S.; Bielawski, J.; Hannun, Y.A.; Ogretmen, B. Antiapoptotic roles of ceramide-synthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2010, 24, 296–308.
88. Uen, Y.-H.; Fang, C.-L.; Lin, C.-C.; Hseu, Y.-C.; Hung, S.-T.; Sun, D.-P.; Lin, K.-Y. Ceramide synthase 6 predicts the prognosis of human gastric cancer: It functions as an oncoprotein by dysregulating the SOCS2/JAK2/STAT3 pathway. Mol. Carcinog. 2018, 57, 1675–1689.
89. Senkal, C.E.; Ponnusamy, S.; Manevich, Y.; Meyers-Needham, M.; Saddoughi, S.A.; Mukhopadyay, A.; Dent, P.; Bielawski, J.; Ogretmen, B. 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. 2011, 286, 42446–42458.
90. Schiffmann, S.; Sandner, J.; Birod, K.; Wobst, I.; Angioni, C.; Ruckhäberle, E.; Kaufmann, M.; Ackermann, H.; Lötsch, J.; Schmidt, H.; et al. Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 2009, 30, 745–752.
91. Ashrafi, G.; Schwarz, T.L. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013, 20, 31–42.
92. Mizushima, N.; Komatsu, M. Autophagy: Renovation of cells and tissues. Cell 2011, 147, 728–741.
93. Orenstein, S.J.; Cuervo, A.M. Chaperone-mediated autophagy: Molecular mechanisms and physiological relevance. Semin. Cell Dev. Biol. 2010, 21, 719–726.
94. Tanida, I. Autophagy basics. Microbiol. Immunol. 2011, 55, 1–11.
95. Farré, J.-C.; Subramani, S. Mechanistic insights into selective autophagy pathways: Lessons from yeast. Nat. Rev. Mol. Cell Biol. 2016, 17, 537–552.
96. He, C.; Klionsky, D.J. Regulation Mechanisms and Signaling Pathways of Autophagy. Annu. Rev. Genet. 2009, 43, 67–93.
97. Fujioka, Y.; Suzuki, S.W.; Yamamoto, H.; Kondo-Kakuta, C.; Kimura, Y.; Hirano, H.; Akada, R.; Inagaki, F.; Ohsumi, Y.; Noda, N.N. Structural basis of starvation-induced assembly of the autophagy initiation complex. Nat. Struct. Mol. Biol. 2014, 21, 513–521.
98. Jung, C.H.; Jun, C.B.; Ro, S.-H.; Kim, Y.-M.; Otto, N.M.; Cao, J.; Kundu, M.; Kim, D.-H. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 2009, 20, 1992–2003.
99. Hosokawa, N.; Hara, T.; Kaizuka, T.; Kishi, C.; Takamura, A.; Miura, Y.; Iemura, S.; Natsume, T.; Takehana, K.; Yamada, N.; et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 2009, 20, 1981–1991.
100. Radoshevich, L.; Murrow, L.; Chen, N.; Fernandez, E.; Roy, S.; Fung, C.; Debnath, J. Atg12 conjugation to Atg3 regulates mitochondrial homeostasis and cell death. Cell 2010, 142, 590–600.
101. Fujita, N.; Itoh, T.; Omori, H.; Fukuda, M.; Noda, T.; Yoshimori, T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol. Biol. Cell 2008, 19, 2092–2100.
102. Hanada, T.; Noda, N.N.; Satomi, Y.; Ichimura, Y.; Fujioka, Y.; Takao, T.; Inagaki, F.; Ohsumi, Y. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J. Biol. Chem. 2007, 282, 37298–37302.
103. Ohsumi, Y. Historical landmarks of autophagy research. Cell Res. 2014, 24, 9–23.
104. Kakuta, S.; Yamamoto, H.; Negishi, L.; Kondo-Kakuta, C.; Hayashi, N.; Ohsumi, Y. Atg9 vesicles recruit vesicle-tethering proteins Trs85 and Ypt1 to the autophagosome formation site. J. Biol. Chem. 2012, 287, 44261–44269.
105. Wang, J.; Menon, S.; Yamasaki, A.; Chou, H.-T.; Walz, T.; Jiang, Y.; Ferro-Novick, S. Ypt1 recruits the Atg1 kinase to the pre-autophagosomal structure. Proc. Natl. Acad. Sci. USA 2013, 110, 9800–9805.
106. Axe, E.L.; Walker, S.A.; Manifava, M.; Chandra, P.; Roderick, H.L.; Habermann, A.; Griffiths, G.; Ktistakis, N.T. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 2008, 182, 685–701.
107. Tanida, I.; Minematsu-Ikeguchi, N.; Ueno, T.; Kominami, E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 2005, 1, 84–91.
108. Miller, D.R.; Thorburn, A. Autophagy and organelle homeostasis in cancer. Dev. Cell 2021, 56, 878–880.
109. Boland, M.L.; Chourasia, A.H.; Macleod, K.F. Mitochondrial dysfunction in cancer. Front. Oncol. 2013, 3, 292.
110. Sena, L.A.; Chandel, N.S. Physiological Roles of Mitochondrial Reactive Oxygen Species. Mol. Cell 2012, 48, 158–167.
111. Trachootham, D.; Alexandre, J.; Huang, P. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat. Rev. Drug Discov. 2009, 8, 579–591.
112. Yoo, S.-M.; Jung, Y.-K. A Molecular Approach to Mitophagy and Mitochondrial Dynamics. Mol. Cells 2018, 41, 18–26.
113. Chan, D.C. Mitochondria: Dynamic Organelles in Disease, Aging, and Development. Cell 2006, 125, 1241–1252.
114. Nunnari, J.; Suomalainen, A. Mitochondria: In Sickness and in Health. Cell 2012, 148, 1145–1159.
115. Daskalaki, I.; Gkikas, I.; Tavernarakis, N. Hypoxia and Selective Autophagy in Cancer Development and Therapy. Front. Cell Dev. Biol. 2018, 6, 104.
116. Twig, G.; Shirihai, O.S. The Interplay Between Mitochondrial Dynamics and Mitophagy. Antioxid. Redox Signal. 2011, 14, 1939–1951.
117. Palikaras, K.; Lionaki, E.; Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 2015, 521, 525–528.
118. Head, B.; Griparic, L.; Amiri, M.; Gandre-Babbe, S.; van der Bliek, A.M. Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J. Cell Biol. 2009, 187, 959–966.
119. Poole, A.C.; Thomas, R.E.; Yu, S.; Vincow, E.S.; Pallanck, L. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS ONE 2010, 5, e10054.
120. Tanaka, A.; Cleland, M.M.; Xu, S.; Narendra, D.P.; Suen, D.-F.; Karbowski, M.; Youle, R.J. Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J. Cell Biol. 2010, 191, 1367–1380.
121. Ziviani, E.; Tao, R.N.; Whitworth, A.J. Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc. Natl. Acad. Sci. USA 2010, 107, 5018–5023.
122. Pickrell, A.M.; Youle, R.J. The Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease. Neuron 2015, 85, 257–273.
123. Jin, S.M.; Lazarou, M.; Wang, C.; Kane, L.A.; Narendra, D.P.; Youle, R.J. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 2010, 191, 933–942.
124. Meissner, C.; Lorenz, H.; Weihofen, A.; Selkoe, D.J.; Lemberg, M.K. The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J. Neurochem. 2011, 117, 856–867.
125. Narendra, D.; Tanaka, A.; Suen, D.-F.; Youle, R.J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 2008, 183, 795–803.
126. Narendra, D.P.; Jin, S.M.; Tanaka, A.; Suen, D.-F.; Gautier, C.A.; Shen, J.; Cookson, M.R.; Youle, R.J. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010, 8, e1000298.
127. Chan, N.C.; Salazar, A.M.; Pham, A.H.; Sweredoski, M.J.; Kolawa, N.J.; Graham, R.L.J.; Hess, S.; Chan, D.C. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 2011, 20, 1726–1737.
128. Chavez-Dominguez, R.; Perez-Medina, M.; Lopez-Gonzalez, J.S.; Galicia-Velasco, M.; Aguilar-Cazares, D. The Double-Edge Sword of Autophagy in Cancer: From Tumor Suppression to Pro-tumor Activity. Front. Oncol. 2020, 10, 578418.
129. Pankiv, S.; Clausen, T.H.; Lamark, T.; Brech, A.; Bruun, J.-A.; Outzen, H.; Øvervatn, A.; Bjørkøy, G.; Johansen, T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 2007, 282, 24131–24145.
130. Kirkin, V.; McEwan, D.G.; Novak, I.; Dikic, I. A Role for Ubiquitin in Selective Autophagy. Mol. Cell 2009, 34, 259–269.
131. Kroemer, G.; Mariño, G.; Levine, B. Autophagy and the Integrated Stress Response. Mol. Cell 2010, 40, 280–293.
132. Panda, P.K.; Mukhopadhyay, S.; Das, D.N.; Sinha, N.; Naik, P.P.; Bhutia, S.K. Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics. Semin. Cell Dev. Biol. 2015, 39, 43–55.
133. Marinković, M.; Šprung, M.; Buljubašić, M.; Novak, I. Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy. Oxid. Med. Cell. Longev. 2018, 2018, 1–18.
134. Lauzier, A.; Jean, S. Autophagic Flux Assessment in Colorectal Cancer Cells. Methods Mol. Biol. Clifton NJ 2018, 1765, 167–175.
135. Pan, H.; Wang, Y.; Na, K.; Wang, Y.; Wang, L.; Li, Z.; Guo, C.; Guo, D.; Wang, X. Autophagic flux disruption contributes to Ganoderma lucidum polysaccharide-induced apoptosis in human colorectal cancer cells via MAPK/ERK activation. Cell Death Dis. 2019, 10, 456.
136. Wang, K.; Gong, Q.; Zhan, Y.; Chen, B.; Yin, T.; Lu, Y.; Zhang, Y.; Wang, H.; Ke, J.; Du, B.; et al. Blockage of autophagic flux and induction of mitochondria fragmentation by paroxetine hydrochloride in lung cancer cells promotes apoptosis via the ROS-MAPK pathway. Front. Cell Dev. Biol. 2020, 7, 397.
137. Heiden, M.G.V.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009, 324, 1029–1033.
138. Warburg, O. On the origin of cancer cells. Science 1956, 123, 309–314.
139. Geschickter, C.F.; Warburg, O. Warburg report on the metabolism of tumors. J. Chem. Educ. 1930, 7, 179.
140. Koppenol, W.H.; Bounds, P.L.; Dang, C.V. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 2011, 11, 325–337.
141. Weinberg, F.; Hamanaka, R.; Wheaton, W.W.; Weinberg, S.; Joseph, J.; Lopez, M.; Kalyanaraman, B.; Mutlu, G.M.; Budinger, G.R.S.; Chandel, N.S. Mitochondrial metabolism and ROS generation are essential for KRAS-mediated tumorigenicity. Proc. Natl. Acad. Sci. USA 2010, 107, 8788–8793.
142. Zhang, C.; Lin, M.; Wu, R.; Wang, X.; Yang, B.; Levine, A.J.; Hu, W.; Feng, Z. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc. Natl. Acad. Sci. USA 2011, 108, 16259–16264.
143. Guo, J.Y.; Karsli-Uzunbas, G.; Mathew, R.; Aisner, S.C.; Kamphorst, J.J.; Strohecker, A.M.; Chen, G.; Price, S.; Lu, W.; Teng, X.; et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev. 2013, 27, 1447–1461.
144. Fujiwara, M.; Marusawa, H.; Wang, H.-Q.; Iwai, A.; Ikeuchi, K.; Imai, Y.; Kataoka, A.; Nukina, N.; Takahashi, R.; Chiba, T. Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene 2008, 27, 6002–6011.
145. Li, C.; Zhang, Y.; Cheng, X.; Yuan, H.; Zhu, S.; Liu, J.; Wen, Q.; Xie, Y.; Liu, J.; Kroemer, G.; et al. PINK1 and PARK2 suppress pancreatic tumorigenesis through control of mitochondrial iron-mediated immunometabolism. Dev. Cell 2018, 46, 441–455.e8.
146. Chourasia, A.H.; Tracy, K.; Frankenberger, C.; Boland, M.L.; Sharifi, M.N.; Drake, L.E.; Sachleben, J.R.; Asara, J.M.; Locasale, J.W.; Karczmar, G.S.; et al. Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO Rep. 2015, 16, 1145–1163.
147. Yuan, X.; Wang, B.; Yang, L.; Zhang, Y. The role of ROS-induced autophagy in hepatocellular carcinoma. Clin. Res. Hepatol. Gastroenterol. 2018, 42.
148. Chen, Y.; McMillan-Ward, E.; Kong, J.; Israels, S.J.; Gibson, S.B. Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. J. Cell Sci. 2007, 120.
149. Zhou, J.; Zhang, L.; Wang, M.; Zhou, L.; Feng, X.; Yu, L.; Lan, J.; Gao, W.; Zhang, C.; Bu, Y.; et al. CPX targeting DJ-1 triggers ROS-induced cell death and protective autophagy in colorectal cancer. Theranostics 2019, 9, 5577–5594.
150. Wang, F.; Xia, X.; Yang, C.; Shen, J.; Mai, J.; Kim, H.-C.; Kirui, D.; Kang, Y.; Fleming, J.B.; Koay, E.J.; et al. SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy. Clin. Cancer Res. 2018, 24, 3176–3185.
151. Levine, B.; Klionsky, D.J. Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev. Cell 2004, 6, 463–477.
152. Mizushima, N.; Levine, B.; Cuervo, A.M.; Klionsky, D.J. Autophagy fights disease through cellular self-digestion. Nature 2008, 451, 1069–1075.
153. Lemasters, J.J. Variants of mitochondrial autophagy: Types 1 and 2 mitophagy and micromitophagy (Type 3). Redox Biol. 2014, 2, 749–754.
154. Dany, M.; Gencer, S.; Nganga, R.; Thomas, R.J.; Oleinik, N.; Baron, K.D.; Szulc, Z.M.; Ruvolo, P.; Kornblau, S.; Andreeff, M.; et al. Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML. Blood 2016, 128, 1944–1958.
155. Dany, M.; Ogretmen, B. Ceramide induced mitophagy and tumor suppression. Biochim. Biophys. Acta BBA Mol. Cell Res. 2015, 1853, 2834–2845.
156. Oleinik, N.; Kim, J.; Roth, B.M.; Selvam, S.P.; Gooz, M.; Johnson, R.H.; Lemasters, J.J.; Ogretmen, B. Mitochondrial protein import is regulated by p17/PERMIT to mediate lipid metabolism and cellular stress. Sci. Adv. 2019, 5, eaax1978.
157. Rao, R.P.; Scheffer, L.; Srideshikan, S.M.; Parthibane, V.; Kosakowska-Cholody, T.; Masood, M.A.; Nagashima, K.; Gudla, P.; Lockett, S.; Acharya, U.; et al. Ceramide transfer protein deficiency compromises organelle function and leads to senescence in primary cells. PLoS ONE 2014, 9, e92142.
158. Teixeira, V.; Medeiros, T.C.; Vilaça, R.; Pereira, A.T.; Chaves, S.R.; Côrte-Real, M.; Moradas-Ferreira, P.; Costa, V. Ceramide signalling impinges on Sit4p and Hog1p to promote mitochondrial fission and mitophagy in Isc1p-deficient cells. Cell. Signal. 2015, 27, 1840–1849.
159. Nguyen, H.; Kuril, S.; Bastian, D.; Kim, J.; Zhang, M.; Vaena, S.G.; Dany, M.; Dai, M.; Heinrichs, J.L.; Daenthanasanmak, A.; et al. Complement C3a and C5a receptors promote GVHD by suppressing mitophagy in recipient dendritic cells. JCI Insight 2018, 3, e121697.
160. Mishra, S.K.; Gao, Y.-G.; Deng, Y.; Chalfant, C.E.; Hinchcliffe, E.H.; Brown, R.E. CPTP: A sphingolipid transfer protein that regulates autophagy and inflammasome activation. Autophagy 2018, 14.
161. Vykoukal, J.; Fahrmann, J.F.; Gregg, J.R.; Tang, Z.; Basourakos, S.; Irajizad, E.; Park, S.; Yang, G.; Creighton, C.J.; Fleury, A.; et al. Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer. Nat. Commun. 2020, 11, 4279.
162. Muñoz-Guardiola, P.; Casas, J.; Megías-Roda, E.; Solé, S.; Perez-Montoyo, H.; Yeste-Velasco, M.; Erazo, T.; Diéguez-Martínez, N.; Espinosa-Gil, S.; Muñoz-Pinedo, C.; et al. The anti-cancer drug ABTl0812 induces er stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells. Autophagy 2020, 1–18.
163. Rogalska, A.; Gajek, A.; Łukawska, M.; Oszczapowicz, I.; Marczak, A. Novel oxazolinoanthracyclines as tumor cell growth inhibitors—Contribution of autophagy and apoptosis in solid tumor cells death. PLoS ONE 2018, 13.
164. Morad, S.A.F.; MacDougall, M.R.; Abdelmageed, N.; Kao, L.-P.; Feith, D.J.; Tan, S.-F.; Kester, M.; Loughran, T.P.; Wang, H.-G.; Cabot, M.C. Pivotal role of mitophagy in response of acute myelogenous leukemia to a ceramide-tamoxifen-containing drug regimen. Exp. Cell Res. 2019, 381, 256–264.
165. Lima, S.; Takabe, K.; Newton, J.; Saurabh, K.; Young, M.M.; Leopoldino, A.M.; Hait, N.C.; Roberts, J.L.; Wang, H.-G.; Dent, P.; et al. TP53 is required for BECN1- and ATG5-dependent cell death induced by sphingosine kinase 1 inhibition. Autophagy 2018, 14, 942–957.
166. Dai, L.; Bai, A.; Smith, C.D.; Rodriguez, P.C.; Yu, F.; Qin, Z. ABC294640, a novel sphingosine kinase 2 inhibitor, induces oncogenic virus-infected cell autophagic death and represses tumor growth. Mol. Cancer Ther. 2017, 16.
167. Karlsson, I.; Zhou, X.; Thomas, R.; Smith, A.T.; Bonner, M.Y.; Bakshi, P.; Banga, A.K.; Bowen, J.P.; Qabaja, G.; Ford, S.L.; et al. Solenopsin A and analogs exhibit ceramide-like biological activity. Vasc. Cell 2015, 7, 5.
168. Wegner, M.-S.; Gruber, L.; Schömel, N.; Trautmann, S.; Brachtendorf, S.; Fuhrmann, D.; Schreiber, Y.; Olesch, C.; Brüne, B.; Geisslinger, G.; et al. GPER1 influences cellular homeostasis and cytostatic drug resistance via influencing long chain ceramide synthesis in breast cancer cells. Int. J. Biochem. Cell Biol. 2019, 112, 95–106.
169. Liu, J.; Beckman, B.S.; Foroozesh, M. A review of ceramide analogs as potential anticancer agents. Future Med. Chem. 2013, 5, 1405–1421.
170. Song, M.; Zang, W.; Zhang, B.; Cao, J.; Yang, G. GCS overexpression is associated with multidrug resistance of human HCT-8 colon cancer cells. J. Exp. Clin. Cancer Res. CR 2012, 31, 23.
171. Liu, Y.Y.; Han, T.Y.; Giuliano, A.E.; Cabot, M.C. Expression of glucosylceramide synthase, converting ceramide to glucosylceramide, confers adriamycin resistance in human breast cancer cells. J. Biol. Chem. 1999, 274, 1140–1146.
172. Liu, Y.-Y.; Yu, J.Y.; Yin, D.; Patwardhan, G.A.; Gupta, V.; Hirabayashi, Y.; Holleran, W.M.; Giuliano, A.E.; Jazwinski, S.M.; Gouaze-Andersson, V.; et al. A role for ceramide in driving cancer cell resistance to doxorubicin. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2008, 22, 2541–2551.
173. Gouazé, V.; Liu, Y.-Y.; Prickett, C.S.; Yu, J.Y.; Giuliano, A.E.; Cabot, M.C. Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs. Cancer Res. 2005, 65, 3861–3867.
174. Shaw, J.J.P.; Boyer, T.L.; Venner, E.; Beck, P.J.; Slamowitz, T.; Caste, T.; Hickman, A.; Raymond, M.H.; Costa-Pinheiro, P.; Jameson, M.J.; et al. Inhibition of lysosomal function mitigates protective mitophagy and augments ceramide nanoliposome–induced cell death in head and neck squamous cell carcinoma. Mol. Cancer Ther. 2020, 19, 2621–2633.
175. Sundaram, K.; Mather, A.R.; Marimuthu, S.; Shah, P.P.; Snider, A.J.; Obeid, L.M.; Hannun, Y.A.; Beverly, L.J.; Siskind, L.J. Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death. Biochem. J. 2016, 473, 743–755.
176. Cartier, A.; Hla, T. Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science 2019, 366.
177. Matloubian, M.; Lo, C.G.; Cinamon, G.; Lesneski, M.J.; Xu, Y.; Brinkmann, V.; Allende, M.L.; Proia, R.L.; Cyster, J.G. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004, 427.
178. Pappu, R.; Schwab, S.R.; Cornelissen, I.; Pereira, J.P.; Regard, J.B.; Xu, Y.; Camerer, E.; Zheng, Y.W.; Huang, Y.; Cyster, J.G.; et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 2007, 316.
179. Brinkmann, V.; Billich, A.; Baumruker, T.; Heining, P.; Schmouder, R.; Francis, G.; Aradhye, S.; Burtin, P. Fingolimod (FTY720): Discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 2010, 9.
180. Carrié, L.; Virazels, M.; Dufau, C.; Montfort, A.; Levade, T.; Ségui, B.; Andrieu-Abadie, N. New insights into the role of sphingolipid metabolism in melanoma. Cells 2020, 9, 1967.
181. Mrad, M.; Imbert, C.; Garcia, V.; Rambow, F.; Therville, N.; Carpentier, S.; Ségui, B.; Levade, T.; Azar, R.; Marine, J.-C.; et al. Downregulation of sphingosine kinase-1 induces protective tumor immunity by promoting m1 macrophage response in melanoma. Oncotarget 2016, 7, 71873–71886.
182. Imbert, C.; Montfort, A.; Fraisse, M.; Marcheteau, E.; Gilhodes, J.; Martin, E.; Bertrand, F.; Marcellin, M.; Burlet-Schiltz, O.; de Peredo, A.G.; et al. Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1. Nat. Commun. 2020, 11, 437.
183. Liu, Y.-N.; Zhang, H.; Zhang, L.; Cai, T.-T.; Huang, D.-J.; He, J.; Ni, H.-H.; Zhou, F.-J.; Zhang, X.-S.; Li, J. Sphingosine 1 phosphate receptor-1 (S1P1) promotes tumor-associated regulatory t cell expansion: Leading to poor survival in bladder cancer. Cell Death Dis. 2019, 10, 50.
184. van der Weyden, L.; Arends, M.J.; Campbell, A.D.; Bald, T.; Wardle-Jones, H.; Griggs, N.; Velasco-Herrera, M.D.C.; Tüting, T.; Sansom, O.J.; Karp, N.A.; et al. Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature 2017, 541, 233–236.
185. Lee, M.S.; Sun, W.; Webb, T.J. Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma. Cells 2020, 9, 1030.
186. Sofi, M.H.; Heinrichs, J.; Dany, M.; Nguyen, H.; Dai, M.; Bastian, D.; Schutt, S.; Wu, Y.; Daenthanasanmak, A.; Gencer, S.; et al. Ceramide synthesis regulates t cell activity and GVHD development. JCI Insight 2017, 2, e91701.
187. Chakraborty, P.; Vaena, S.G.; Thyagarajan, K.; Chatterjee, S.; Al-Khami, A.; Selvam, S.P.; Nguyen, H.; Kang, I.; Wyatt, M.W.; Baliga, U.; et al. Pro-survival lipid sphingosine-1-phosphate metabolically programs T cells to limit anti-tumor activity. Cell Rep. 2019, 28, 1879–1893.e7.
188. Chatterjee, S.; Daenthanasanmak, A.; Chakraborty, P.; Wyatt, M.W.; Dhar, P.; Selvam, S.P.; Fu, J.; Zhang, J.; Nguyen, H.; Kang, I.; et al. CD38-NAD+axis regulates immunotherapeutic anti-tumor T cell response. Cell Metab. 2018, 27, 85–100.e8.
189. Barth, B.M.; Wang, W.; Toran, P.T.; Fox, T.E.; Annageldiyev, C.; Ondrasik, R.M.; Keasey, N.R.; Brown, T.J.; Devine, V.G.; Sullivan, E.C.; et al. Sphingolipid metabolism determines the therapeutic efficacy of nanoliposomal ceramide in acute myeloid leukemia. Blood Adv. 2019, 3, 2598–2603.