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Ceramide-orchestrated signalling in cancer cells

Key Points

  • Ceramide is a sphingolipid consisting of sphingosine, an 18-carbon unsaturated amino alcohol hydrocarbon chain, which is joined by an amide linkage to a fatty acid of varying chain length and a varying degree of saturation. The type of fatty acyl group that is attached often dictates the biological activities of ceramide.

  • Through its capacity to induce programmed cell death (apoptosis), ceramide can function as a potent tumour suppressor lipid. Ceramide can also limit cancer cell proliferation by blocking cell cycle transition. Ceramide can also instigate autophagic responses in cancer cells; however, these may yield survival or lethal outcomes.

  • Cancer cells exert tight control over the metabolism of ceramide. As a survival mode, cancer cells upregulate enzymes that metabolize ceramide, which results in muted apoptotic responses and/or the promotion of mitogenicity, depending on the routes by which ceramide is metabolized.

  • Ceramide signalling in cancer cells enlists extrinsic signalling, which originates outside the cell, or intrinsic signalling (also known as the mitochondrial pathway) that originates from within the cell, to signal to downstream beacons of cellular response. These responses can be caspase (protease)-dependent or caspase-independent.

  • Key players in ceramide signalling in cancer are protein phosphatase 2A, p38, JUN N-terminal kinase (JNK), AKT, protein kinase Cζ (PKCζ) and survivin, proteins that communicate and reinforce tumour cell demise and/or the arrest of the cell cycle at G1 and G2 phases.

  • Because of its ability to induce apoptosis, ceramide holds promise as an anticancer agent. Ceramide-based therapies are being developed through the use of ceramide-generating agents, such as fenretinide, and by the use of exogenous cell-permeable short-chain ceramides, such as C6 ceramide. With both avenues, the effect of ceramide can be magnified by the inclusion of agents that block cancer cell-mediated elimination of ceramide.


One crucial barrier to progress in the treatment of cancer has been the inability to control the balance between cell proliferation and apoptosis: enter ceramide. Discoveries over the past 15 years have elevated this sphingolipid to the lofty position of a regulator of cell fate. Ceramide, it turns out, is a powerful tumour suppressor, potentiating signalling events that drive apoptosis, autophagic responses and cell cycle arrest. However, defects in ceramide generation and metabolism in cancer cells contribute to tumour cell survival and resistance to chemotherapy. This Review focuses on ceramide signalling and the targeting of specific metabolic junctures to amplify the tumour suppressive activities of ceramide. The potential of ceramide-based therapeutics in the treatment of cancer is also discussed.

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Figure 1: De novo biosynthesis of ceramide.
Figure 2: Ceramide metabolism and points of intervention.
Figure 3: Extrinsic and intrinsic pathways of ceramide-driven apoptosis in cancer.
Figure 4: Pathways of ceramide-driven autophagic response.
Figure 5: The effect of ceramide on cell cycle progression.


  1. 1

    Levy, M. & Futerman, A. H. Mammalian ceramide synthases. IUBMB Life 62, 347–356 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  2. 2

    Tettamanti, G., Bassi, R., Viani, P. & Riboni, L. Salvage pathways in glycosphingolipid metabolism. Biochimie 85, 423–437 (2003).

    CAS  Google Scholar 

  3. 3

    Kitatani, K., Idkowiak-Baldys, J. & Hannun, Y. A. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell. Signal. 20, 1010–1018 (2008).

    CAS  Google Scholar 

  4. 4

    Mullen, T. D., Hannun, Y. A. & Obeid, L. M. Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem. J. 441, 789–802 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  5. 5

    Senchenkov, A., Litvak, D. A. & Cabot, M. C. Targeting ceramide metabolism-a strategy for overcoming drug resistance. J. Natl Cancer Inst. 93, 347–357 (2001).

    CAS  Google Scholar 

  6. 6

    Kolesnick, R. & Fuks, Z. Radiation and ceramide-induced apoptosis. Oncogene 22, 5897–5906 (2003).

    CAS  Google Scholar 

  7. 7

    Truman, J. P. et al. Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis. J. Biol. Chem. 280, 23262–23272 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  8. 8

    Hannun, Y. A. & Obeid, L. M. Many ceramides. J. Biol. Chem. 286, 27855–27862 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  9. 9

    Tidhar, R. et al. Acyl chain specificity of ceramide synthases is determined within a region of 150 residues in the Tram-Lag-CLN8 (TLC) domain. J. Biol. Chem. 287, 3197–3206 (2012).

    CAS  Google Scholar 

  10. 10

    Grosch, S., Schiffmann, S. & Geisslinger, G. Chain length-specific properties of ceramides. Prog. Lipid Res. 51, 50–62 (2012).

    Google Scholar 

  11. 11

    Siddique, M. M. et al. Ablation of dihydroceramide desaturase confers resistance to Etoposide-induced apoptosis in vitro. PLoS ONE 7, e44042 (2012). This work defines the importance of the 4,5- trans double bond in cell survival and sensitivity to anticancer agents, and thus exemplifies intricate points of ceramide molecular species specificity.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. 12

    Liu, Y. Y. et al. Glycosylation of ceramide potentiates cellular resistance to tumor necrosis factor-α-induced apoptosis. Exp. Cell Res. 252, 464–470 (1999). This paper describes for the first time the therapeutic impact of targeting GCS to confer resistance to TNF.

    CAS  Google Scholar 

  13. 13

    Bleicher, R. J. & Cabot, M. C. Glucosylceramide synthase and apoptosis. Biochim. Biophys. Acta 1585, 172–178 (2002).

    CAS  Google Scholar 

  14. 14

    Meng, A. et al. Sphingomyelin synthase as a potential target for D609-induced apoptosis in U937 human monocytic leukemia cells. Exp. Cell Res. 292, 385–392 (2004).

    CAS  Google Scholar 

  15. 15

    Mitra, P. et al. Ceramide kinase regulates growth and survival of A549 human lung adenocarcinoma cells. FEBS Lett. 581, 735–740 (2007). This paper shows that CERK controls the balance between pro-apoptotic ceramide and anti-apoptotic ceramide 1-phosphate to regulate the growth and survival of cancer cells.

    CAS  Google Scholar 

  16. 16

    Kolesnick, R. N. & Hemer, M. R. Characterization of a ceramide kinase activity from human leukemia (HL-60) cells. Separation from diacylglycerol kinase activity. J. Biol. Chem. 265, 18803–18808 (1990). This paper is the first record of CERK activity distinct from diacylglycerol kinase activity, as shown in a leukaemia cell model.

    CAS  Google Scholar 

  17. 17

    Gomez-Munoz, A. Ceramide 1-phosphate/ceramide, a switch between life and death. Biochim. Biophys. Acta 1758, 2049–2056 (2006).

    CAS  Google Scholar 

  18. 18

    Bornancin, F. Ceramide kinase: the first decade. Cell. Signal. 23, 999–1008 (2011).

    CAS  Google Scholar 

  19. 19

    Wang, H. et al. N-(4-Hydroxyphenyl)retinamide increases dihydroceramide and synergizes with dimethylsphingosine to enhance cancer cell killing. Mol. Cancer Ther. 7, 2967–2976 (2008).

    CAS  Google Scholar 

  20. 20

    Sun, W. et al. Alkaline ceramidase 2 regulates β1 integrin maturation and cell adhesion. FASEB J. 23, 656–666 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  21. 21

    Pyne, N. J. & Pyne, S. Sphingosine 1-phosphate and cancer. Nature Rev. Cancer 10, 489–503 (2010).

    CAS  Google Scholar 

  22. 22

    Liu, X. et al. Acid ceramidase inhibition: a novel target for cancer therapy. Front. Biosci. 13, 2293–2298 (2008).

    CAS  Google Scholar 

  23. 23

    Liu, X. et al. Acid ceramidase upregulation in prostate cancer: role in tumor development and implications for therapy. Expert Opin. Ther. Targets 13, 1449–1458 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  24. 24

    Flowers, M. et al. C6-Ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth. Breast Cancer Res. Treat. 133, 447–458 (2011).

    Google Scholar 

  25. 25

    Gouaze-Andersson, V. et al. Inhibition of acid ceramidase by a 2-substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4-hydroxyphenyl) retinamide. Prostate 71, 1064–1073 (2011).

    CAS  Google Scholar 

  26. 26

    Morad, S. A. et al. Ceramide-antiestrogen nanoliposomal combinations - novel impact of hormonal therapy in hormone-insensitive breast cancer. Mol Cancer Ther 11, 2352–2361 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  27. 27

    Gatt, S. Enzymic Hydrolysis and Synthesis of Ceramides. J. Biol. Chem. 238, 3131–3133 (1963).

    CAS  Google Scholar 

  28. 28

    Baran, Y. et al. Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells. J. Biol. Chem. 282, 10922–10934 (2007).

    CAS  PubMed  Google Scholar 

  29. 29

    Canals, D., Perry, D. M., Jenkins, R. W. & Hannun, Y. A. Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases. Br. J. Pharmacol. 163, 694–712 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  30. 30

    Kolesnick, R., Altieri, D. & Fuks, Z. A. CERTain role for ceramide in taxane-induced cell death. Cancer Cell 11, 473–475 (2007).

    CAS  Google Scholar 

  31. 31

    Charles, A. G. et al. Taxol-induced ceramide generation and apoptosis in human breast cancer cells. Cancer Chemother. Pharmacol. 47, 444–450 (2001).

    CAS  Google Scholar 

  32. 32

    Zeidan, Y. H., Jenkins, R. W. & Hannun, Y. A. Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway. J. Cell Biol. 181, 335–350 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  33. 33

    Rothstein, T. L. Inducible resistance to Fas-mediated apoptosis in B cells. Cell Res. 10, 245–266 (2000).

    CAS  Google Scholar 

  34. 34

    Thorburn, A., Behbakht, K. & Ford, H. TRAIL receptor-targeted therapeutics: resistance mechanisms and strategies to avoid them. Drug Resist. Updat. 11, 17–24 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  35. 35

    Zhang, L. & Fang, B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 12, 228–237 (2005).

    CAS  Google Scholar 

  36. 36

    Park, M. A. et al. Vorinostat and sorafenib increase CD95 activation in gastrointestinal tumor cells through a Ca2+ -de novo ceramide-PP2A-reactive oxygen species-dependent signaling pathway. Cancer Res. 70, 6313–6324 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  37. 37

    Park, M. A. et al. Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation. Cancer Biol. Ther. 7, 1648–1662 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  38. 38

    Huang, S. T., Yang, R. C., Chen, M. Y. & Pang, J. H. Phyllanthus urinaria induces the Fas receptor/ligand expression and ceramide-mediated apoptosis in HL-60 cells. Life Sci. 75, 339–351 (2004).

    CAS  Google Scholar 

  39. 39

    Dumitru, C. A. & Gulbins, E. TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 25, 5612–5625 (2006). This paper demonstrates that TRAIL activates acid sphingomyelinase via a mechanism involving reactive oxygen species that results in release of ceramide and formation of ceramide-enriched membrane platforms.

    CAS  Google Scholar 

  40. 40

    Miyaji, M. et al. Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis. J. Exp. Med. 202, 249–259 (2005). This paper reported that membrane sphingomyelin is important for FAS clustering through aggregation of ceramide-enriched membrane platforms, leading to FAS-mediated apoptosis.

    CAS  PubMed Central  PubMed  Google Scholar 

  41. 41

    Grassme, H. et al. CD95 signaling via ceramide-rich membrane rafts. J. Biol. Chem. 276, 20589–20596 (2001). This paper shows that CD95-mediated clustering by ceramide is a prerequisite for signalling and cell death.

    CAS  Google Scholar 

  42. 42

    Stancevic, B. & Kolesnick, R. Ceramide-rich platforms in transmembrane signaling. FEBS Lett. 584, 1728–1740 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  43. 43

    Cremesti, A. et al. Ceramide enables fas to cap and kill. J. Biol. Chem. 276, 23954–23961 (2001).

    CAS  Google Scholar 

  44. 44

    Dumitru, C. A., Carpinteiro, A., Trarbach, T., Hengge, U. R. & Gulbins, E. Doxorubicin enhances TRAIL-induced cell death via ceramide-enriched membrane platforms. Apoptosis 12, 1533–1541 (2007).

    CAS  Google Scholar 

  45. 45

    Min, Y. et al. Death receptor 5-recruited raft components contributes to the sensitivity of Jurkat leukemia cell lines to TRAIL-induced cell death. IUBMB Life 61, 261–267 (2009).

    CAS  Google Scholar 

  46. 46

    Grassme, H., Schwarz, H. & Gulbins, E. Molecular mechanisms of ceramide-mediated CD95 clustering. Biochem. Biophys. Res. Commun. 284, 1016–1030 (2001).

    CAS  Google Scholar 

  47. 47

    Grassme, H., Cremesti, A., Kolesnick, R. & Gulbins, E. Ceramide-mediated clustering is required for CD95-DISC formation. Oncogene 22, 5457–5470 (2003).

    CAS  Google Scholar 

  48. 48

    Schaefer, J. T., Barthlen, W. & Schweizer, P. Ceramide induces apoptosis in neuroblastoma cell cultures resistant to CD95 (Fas/APO-1)-mediated apoptosis. J. Pediatr. Surg. 35, 473–479 (2000).

    CAS  Google Scholar 

  49. 49

    Herr, I., Wilhelm, D., Bohler, T., Angel, P. & Debatin, K. M. Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J. 16, 6200–6208 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  50. 50

    Wagenknecht, B., Roth, W., Gulbins, E., Wolburg, H. & Weller, M. C2-ceramide signaling in glioma cells: synergistic enhancement of CD95-mediated, caspase-dependent apoptosis. Cell Death Differ. 8, 595–602 (2001).

    CAS  Google Scholar 

  51. 51

    Zhang, Y., Yoshida, T. & Zhang, B. TRAIL induces endocytosis of its death receptors in MDA-MB-231 breast cancer cells. Cancer Biol. Ther. 8, 917–922 (2009).

    CAS  Google Scholar 

  52. 52

    White-Gilbertson, S. et al. Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells. Oncogene 28, 1132–1141 (2009). This paper reports the potential of modulation of CERS6 as a therapeutic strategy to alter apoptotic susceptibility.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. 53

    Voelkel-Johnson, C., Hannun, Y. A. & El-Zawahry, A. Resistance to TRAIL is associated with defects in ceramide signaling that can be overcome by exogenous C6-ceramide without requiring down-regulation of cellular FLICE inhibitory protein. Mol. Cancer Ther. 4, 1320–1327 (2005).

    CAS  Google Scholar 

  54. 54

    Asakuma, J., Sumitomo, M., Asano, T. & Hayakawa, M. Selective Akt inactivation and tumor necrosis actor-related apoptosis-inducing ligand sensitization of renal cancer cells by low concentrations of paclitaxel. Cancer Res. 63, 1365–1370 (2003).

    CAS  Google Scholar 

  55. 55

    Colell, A., Morales, A., Fernandez-Checa, J. C. & Garcia-Ruiz, C. Ceramide generated by acidic sphingomyelinase contributes to tumor necrosis factor-α-mediated apoptosis in human colon HT-29 cells through glycosphingolipids formation. Possible role of ganglioside GD3. FEBS Lett. 526, 135–141 (2002).

    CAS  Google Scholar 

  56. 56

    Cai, Z. et al. Alteration of the sphingomyelin/ceramide pathway is associated with resistance of human breast carcinoma MCF7 cells to tumor necrosis factor-α-mediated cytotoxicity. J. Biol. Chem. 272, 6918–6926 (1997).

    CAS  Google Scholar 

  57. 57

    Autelli, R. et al. Divergent pathways for TNF and C2-ceramide toxicity in HTC hepatoma cells. Biochim. Biophys. Acta 1793, 1182–1190 (2009).

    CAS  Google Scholar 

  58. 58

    Higuchi, M., Singh, S., Jaffrezou, J. P. & Aggarwal, B. B. Acidic sphingomyelinase-generated ceramide is needed but not sufficient for TNF-induced apoptosis and nuclear factor-κ B activation. J. Immunol. 157, 297–304 (1996).

    CAS  Google Scholar 

  59. 59

    Kuroki, J. et al. Cell-permeable ceramide inhibits the growth of B lymphoma Raji cells lacking TNF-α-receptors by inducing G0/G1 arrest but not apoptosis: a new model for dissecting cell-cycle arrest and apoptosis. Leukemia 10, 1950–1958 (1996).

    CAS  Google Scholar 

  60. 60

    Lamour, N. F. et al. Ceramide kinase regulates the production of tumor necrosis factor α (TNFα) via inhibition of TNFα-converting enzyme. J. Biol. Chem. 286, 42808–42817 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  61. 61

    Donato, N. J. & Klostergaard, J. Distinct stress and cell destruction pathways are engaged by TNF and ceramide during apoptosis of MCF-7 cells. Exp. Cell Res. 294, 523–533 (2004).

    CAS  Google Scholar 

  62. 62

    Guo, Y. L., Kang, B., Yang, L. J. & Williamson, J. R. Tumor necrosis factor-α and ceramide induce cell death through different mechanisms in rat mesangial cells. Am. J. Physiol. 276, F390–F397 (1999).

    CAS  Google Scholar 

  63. 63

    Karasavvas, N. & Zakeri, Z. Relationships of apoptotic signaling mediated by ceramide and TNF-α in U937 cells. Cell Death Differ. 6, 115–123 (1999).

    CAS  Google Scholar 

  64. 64

    Kimura, K., Markowski, M., Edsall, L. C., Spiegel, S. & Gelmann, E. P. Role of ceramide in mediating apoptosis of irradiated LNCaP prostate cancer cells. Cell Death Differ. 10, 240–248 (2003).

    CAS  Google Scholar 

  65. 65

    Goswami, R., Kilkus, J., Scurlock, B. & Dawson, G. CrmA protects against apoptosis and ceramide formation in PC12 cells. Neurochem. Res. 27, 735–741 (2002).

    CAS  Google Scholar 

  66. 66

    De Nadai, C. et al. Nitric oxide inhibits tumor necrosis factor-α-induced apoptosis by reducing the generation of ceramide. Proc. Natl Acad. Sci. USA 97, 5480–5485 (2000).

    CAS  Google Scholar 

  67. 67

    Sawada, M. et al. Molecular mechanisms of TNF-α-induced ceramide formation in human glioma cells: P53-mediated oxidant stress-dependent and -independent pathways. Cell Death Differ. 11, 997–1008 (2004).

    CAS  Google Scholar 

  68. 68

    Yoon, G. et al. Ceramide increases Fas-mediated apoptosis in glioblastoma cells through FLIP down-regulation. J. Neurooncol 60, 135–141 (2002).

    Google Scholar 

  69. 69

    Nam, S. Y., Amoscato, A. A. & Lee, Y. J. Low glucose-enhanced TRAIL cytotoxicity is mediated through the ceramide-Akt-FLIP pathway. Oncogene 21, 337–346 (2002).

    CAS  Google Scholar 

  70. 70

    Rippo, M. R. et al. FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells. Oncogene 23, 7753–7760 (2004).

    CAS  Google Scholar 

  71. 71

    Zhou, X. D. et al. Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma. Clin. Sci. 106, 397–405 (2004).

    CAS  Google Scholar 

  72. 72

    Babiychuk, E. B. et al. The targeting of plasmalemmal ceramide to mitochondria during apoptosis. PLoS ONE 6, e23706 (2011). This paper describes how plasmalemmal ceramide reaches mitochondria and induces apoptosis.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. 73

    Babiychuk, E. B., Monastyrskaya, K. & Draeger, A. Fluorescent annexin A1 reveals dynamics of ceramide platforms in living cells. Traffic 9, 1757–1775 (2008).

    CAS  Google Scholar 

  74. 74

    Stiban, J., Caputo, L. & Colombini, M. Ceramide synthesis in the endoplasmic reticulum can permeabilize mitochondria to proapoptotic proteins. J. Lipid Res. 49, 625–634 (2008). This paper reports the link between ceramide synthesis in the ER and ceramide-mitochondrial apoptosis.

    CAS  Google Scholar 

  75. 75

    Bionda, C., Portoukalian, J., Schmitt, D., Rodriguez-Lafrasse, C. & Ardail, D. Subcellular compartmentalization of ceramide metabolism: MAM (mitochondria-associated membrane) and/or mitochondria? Biochem. J. 382, 527–533 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  76. 76

    Novgorodov, S. A. et al. Novel pathway of ceramide production in mitochondria: thioesterase and neutral ceramidase produce ceramide from sphingosine and acyl-CoA. J. Biol. Chem. 286, 25352–25362 (2011). This paper reports a novel pathway of ceramide production in mitochondria.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. 77

    Wu, B. X., Rajagopalan, V., Roddy, P. L., Clarke, C. J. & Hannun, Y. A. Identification and characterization of murine mitochondria-associated neutral sphingomyelinase (MA-nSMase), the mammalian sphingomyelin phosphodiesterase 5. J. Biol. Chem. 285, 17993–18002 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  78. 78

    Birbes, H., El Bawab, S., Hannun, Y. A. & Obeid, L. M. Selective hydrolysis of a mitochondrial pool of sphingomyelin induces apoptosis. FASEB J. 15, 2669–2679 (2001).

    CAS  Google Scholar 

  79. 79

    Siskind, L. J., Kolesnick, R. N. & Colombini, M. Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J. Biol. Chem. 277, 26796–26803 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  80. 80

    Siskind, L. J., Kolesnick, R. N. & Colombini, M. Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion 6, 118–125 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  81. 81

    Siskind, L. J. & Colombini, M. The lipids C2− and C16-ceramide form large stable channels. Implications for apoptosis. J. Biol. Chem. 275, 38640–38644 (2000). This paper is the first report of stable pore formation by a lipid in a membrane.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. 82

    Ganesan, V. et al. Ceramide and activated Bax act synergistically to permeabilize the mitochondrial outer membrane. Apoptosis 15, 553–562 (2010). This paper reports the role of both ceramide and BCL-2 family proteins in permeabilization of the outer mitochondrial membrane.

    CAS  PubMed Central  PubMed  Google Scholar 

  83. 83

    von Haefen, C. et al. Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 21, 4009–4019 (2002). This paper reports that BAX is a key activator of ceramide-mediated cancer cell death pathways.

    CAS  Google Scholar 

  84. 84

    Lee, H. et al. Mitochondrial ceramide-rich macrodomains functionalize Bax upon irradiation. PLoS ONE 6, e19783 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  85. 85

    Martinez-Abundis, E., Correa, F., Pavon, N. & Zazueta, C. Bax distribution into mitochondrial detergent-resistant microdomains is related to ceramide and cholesterol content in postischemic hearts. FEBS J. 276, 5579–5588 (2009).

    CAS  Google Scholar 

  86. 86

    Belaud-Rotureau, M. A. et al. Early transitory rise in intracellular pH leads to Bax conformation change during ceramide-induced apoptosis. Apoptosis 5, 551–560 (2000).

    CAS  Google Scholar 

  87. 87

    Tsuruta, F. et al. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J. 23, 1889–1899 (2004). This paper reveals a key role of BAX in the regulation of stress-induced apoptosis.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. 88

    Yoshida, K., Yamaguchi, T., Natsume, T., Kufe, D. & Miki, Y. JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nature Cell Biol. 7, 278–285 (2005).

    CAS  Google Scholar 

  89. 89

    Kong, J. Y., Klassen, S. S. & Rabkin, S. W. Ceramide activates a mitochondrial p38 mitogen-activated protein kinase: a potential mechanism for loss of mitochondrial transmembrane potential and apoptosis. Mol. Cell Biochem. 278, 39–51 (2005).

    CAS  Google Scholar 

  90. 90

    Kim, H. J., Oh, J. E., Kim, S. W., Chun, Y. J. & Kim, M. Y. Ceramide induces p38 MAPK-dependent apoptosis and Bax translocation via inhibition of Akt in HL-60 cells. Cancer Lett. 260, 88–95 (2008). This paper demonstrates that ceramide-induced p38 MAPK activation negatively regulates the AKT pathway.

    CAS  Google Scholar 

  91. 91

    Lin, C. F. et al. GSK-3β acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis. J. Cell Sci. 120, 2935–2943 (2007). This paper reports a role for GSK3β in ceramide-induced mitochondrial apoptosis.

    CAS  Google Scholar 

  92. 92

    Sanvicens, N. & Cotter, T. G. Ceramide is the key mediator of oxidative stress-induced apoptosis in retinal photoreceptor cells. J. Neurochem. 98, 1432–1444 (2006).

    CAS  Google Scholar 

  93. 93

    De Stefanis, D. et al. Increase in ceramide level alters the lysosomal targeting of cathepsin D prior to onset of apoptosis in HT-29 colon cancer cells. Biol. Chem. 383, 989–999 (2002).

    CAS  Google Scholar 

  94. 94

    Heinrich, M. et al. Ceramide as an activator lipid of cathepsin D. Adv. Exp. Med. Biol. 477, 305–315 (2000).

    CAS  PubMed  Google Scholar 

  95. 95

    Heinrich, M. et al. Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J. 18, 5252–5263 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  96. 96

    Darios, F., Lambeng, N., Troadec, J. D., Michel, P. P. & Ruberg, M. Ceramide increases mitochondrial free calcium levels via caspase 8 and Bid: role in initiation of cell death. J. Neurochem. 84, 643–654 (2003).

    CAS  Google Scholar 

  97. 97

    Yuan, H., Williams, S. D., Adachi, S., Oltersdorf, T. & Gottlieb, R. A. Cytochrome c dissociation and release from mitochondria by truncated Bid and ceramide. Mitochondrion 2, 237–244 (2003).

    CAS  Google Scholar 

  98. 98

    Lin, C. F. et al. Bcl-2 rescues ceramide- and etoposide-induced mitochondrial apoptosis through blockage of caspase-2 activation. J. Biol. Chem. 280, 23758–23765 (2005).

    CAS  Google Scholar 

  99. 99

    Sumitomo, M. et al. Protein kinase Cδ amplifies ceramide formation via mitochondrial signaling in prostate cancer cells. J. Clin. Invest. 109, 827–836 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  100. 100

    Pinton, P. et al. The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J. 20, 2690–2701 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  101. 101

    Raisova, M. et al. Resistance to CD95/Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release. FEBS Lett. 473, 27–32 (2000).

    CAS  Google Scholar 

  102. 102

    Morales, M. C. et al. 4-HPR-mediated leukemia cell cytotoxicity is triggered by ceramide-induced mitochondrial oxidative stress and is regulated downstream by Bcl-2. Free Radic. Res. 41, 591–601 (2007).

    CAS  Google Scholar 

  103. 103

    Hockenbery, D. M. Targeting mitochondria for cancer therapy. Environ. Mol. Mutagen. 51, 476–489 (2010).

    CAS  Google Scholar 

  104. 104

    Johnstone, R. W., Ruefli, A. A. & Lowe, S. W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153–164 (2002).

    CAS  PubMed  Google Scholar 

  105. 105

    Kang, M. H. & Reynolds, C. P. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin. Cancer Res. 15, 1126–1132 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  106. 106

    Yu, T., Li, J., Qiu, Y. & Sun, H. 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) facilitates curcumin-induced melanoma cell apoptosis by enhancing ceramide accumulation, JNK activation, and inhibiting PI3K/AKT activation. Mol. Cell. Biochem. 361, 47–54 (2012).

    CAS  Google Scholar 

  107. 107

    Jiang, Y. et al. Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer Biol. Ther. 12, 574–585 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  108. 108

    Zhu, Q. Y. et al. C6-ceramide synergistically potentiates the anti-tumor effects of histone deacetylase inhibitors via AKT dephosphorylation and α-tubulin hyperacetylation both in vitro and in vivo. Cell Death Dis. 2, e117 (2011).

    PubMed Central  PubMed  Google Scholar 

  109. 109

    Tagaram, H. R. et al. Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut 60, 695–701 (2011). This paper shows that nanoliposomal ceramide is an efficacious antineoplastic agent in an in vivo model of human hepatocellular carcinoma.

    CAS  Google Scholar 

  110. 110

    Kim, S. W., Kim, H. J., Chun, Y. J. & Kim, M. Y. Ceramide produces apoptosis through induction of p27(kip1) by protein phosphatase 2A-dependent Akt dephosphorylation in PC-3 prostate cancer cells. J. Toxicol. Environ. Health A 73, 1465–1476 (2010).

    CAS  Google Scholar 

  111. 111

    Blouin, C. M. et al. Plasma membrane subdomain compartmentalization contributes to distinct mechanisms of ceramide action on insulin signaling. Diabetes 59, 600–610 (2010).

    CAS  Google Scholar 

  112. 112

    Bourbon, N. A., Yun, J. & Kester, M. Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex. J. Biol. Chem. 275, 35617–35623 (2000).

    CAS  Google Scholar 

  113. 113

    Powell, D. J., Hajduch, E., Kular, G. & Hundal, H. S. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol. Cell. Biol. 23, 7794–7808 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  114. 114

    Bourbon, N. A., Sandirasegarane, L. & Kester, M. Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J. Biol. Chem. 277, 3286–3292 (2002). This paper demonstrates that ceramide downregulates AKT through PKCζ.

    CAS  Google Scholar 

  115. 115

    Fox, T. E. et al. Ceramide recruits and activates protein kinase C zeta (PKC zeta) within structured membrane microdomains. J. Biol. Chem. 282, 12450–12457 (2007). This paper demonstrates that structured membrane microdomains are necessary for ceramide-induced activation of PKCζ and resultant diminished AKT activity.

    CAS  PubMed  Google Scholar 

  116. 116

    Dobrowsky, R. T., Kamibayashi, C., Mumby, M. C. & Hannun, Y. A. Ceramide activates heterotrimeric protein phosphatase 2A. J. Biol. Chem. 268, 15523–15530 (1993). This paper is the first demonstration that ceramide activation of heterotrimeric PP2A requires the presence of a B subunit.

    CAS  Google Scholar 

  117. 117

    Mukhopadhyay, A. et al. Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling. FASEB J. 23, 751–763 (2009). This paper shows that regulation of PP2A signalling involves direct interaction between ceramide and inhibitor 2.

    CAS  PubMed Central  PubMed  Google Scholar 

  118. 118

    Kuo, Y. C. et al. Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55α regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt. J. Biol. Chem. 283, 1882–1892 (2008).

    CAS  Google Scholar 

  119. 119

    Ugi, S. et al. Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes. Mol. Cell. Biol. 24, 8778–8789 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  120. 120

    Zhang, Q. J. et al. Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. Diabetes 61, 1848–1859 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  121. 121

    Chen, C. L. et al. Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway. Blood 111, 4365–4374 (2008). This paper reports that TXNIP is involved in ceramide-induced p38 MAPK and JNK phosphorylation and cell death.

    CAS  Google Scholar 

  122. 122

    Messner, M. C. & Cabot, M. C. Cytotoxic responses to N-(4-hydroxyphenyl)retinamide in human pancreatic cancer cells. Cancer Chemother. Pharmacol. 68, 477–487 (2011).

    CAS  Google Scholar 

  123. 123

    Mondal, S., Mandal, C., Sangwan, R. & Chandra, S. Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Mol. Cancer 9, 239 (2010).

    PubMed Central  PubMed  Google Scholar 

  124. 124

    Hilchie, A. L. et al. Curcumin-induced apoptosis in PC3 prostate carcinoma cells is caspase-independent and involves cellular ceramide accumulation and damage to mitochondria. Nutr. Cancer 62, 379–389 (2010).

    CAS  Google Scholar 

  125. 125

    Maziere, C. et al. UVA radiation stimulates ceramide production: relationship to oxidative stress and potential role in ERK, JNK, and p38 activation. Biochem. Biophys. Res. Commun. 281, 289–294 (2001).

    CAS  Google Scholar 

  126. 126

    Sanchez, A. M. et al. Apoptosis induced by capsaicin in prostate PC-3 cells involves ceramide accumulation, neutral sphingomyelinase, and JNK activation. Apoptosis 12, 2013–2024 (2007).

    CAS  Google Scholar 

  127. 127

    Takeda, K. et al. Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1. J. Biol. Chem. 282, 7522–7531 (2007).

    CAS  Google Scholar 

  128. 128

    Pruschy, M. et al. Ceramide triggers p53-dependent apoptosis in genetically defined fibrosarcoma tumour cells. Br. J. Cancer 80, 693–698 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  129. 129

    Kim, S. S. et al. P53 mediates ceramide-induced apoptosis in SKN-SH cells. Oncogene 21, 2020–2028 (2002).

    CAS  Google Scholar 

  130. 130

    Deng, X., Gao, F. & May, W. S. Protein phosphatase 2A inactivates Bcl2's antiapoptotic function by dephosphorylation and up-regulation of Bcl2-p53 binding. Blood 113, 422–428 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  131. 131

    Temme, A. et al. Nuclear localization of Survivin renders HeLa tumor cells more sensitive to apoptosis by induction of p53 and Bax. Cancer Lett. 250, 177–193 (2007).

    CAS  Google Scholar 

  132. 132

    Blanc-Brude, O. P. et al. Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clin. Cancer Res. 9, 2683–2692 (2003).

    CAS  Google Scholar 

  133. 133

    Mesri, M. et al. Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting. Am. J. Pathol. 158, 1757–1765 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  134. 134

    Liu, X. et al. Targeting of survivin by nanoliposomal ceramide induces complete remission in a rat model of NK-LGL leukemia. Blood 116, 4192–4201 (2010). This paper reports the therapeutic impact of nanoliposomal ceramide in NK-LGL leukaemia and the role of survivin downregulation.

    CAS  PubMed Central  PubMed  Google Scholar 

  135. 135

    McKenzie, J. A., Liu, T., Goodson, A. G. & Grossman, D. Survivin enhances motility of melanoma cells by supporting Akt activation and α5 integrin upregulation. Cancer Res. 70, 7927–7937 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  136. 136

    Shaner, R. L. et al. Quantitative analysis of sphingolipids for lipidomics using triple quadrupole and quadrupole linear ion trap mass spectrometers. J. Lipid Res. 50, 1692–1707 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  137. 137

    Scarlatti, F. et al. Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J. Biol. Chem. 279, 18384–18391 (2004). This paper describes the pivotal role of AKT1in ceramide-induced autophagy.

    CAS  Google Scholar 

  138. 138

    Pattingre, S., Bauvy, C., Levade, T., Levine, B. & Codogno, P. Ceramide-induced autophagy: to junk or to protect cells? Autophagy 5, 558–560 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  139. 139

    Guenther, G. G. et al. Ceramide starves cells to death by downregulating nutrient transporter proteins. Proc. Natl Acad. Sci. USA 105, 17402–17407 (2008).

    CAS  Google Scholar 

  140. 140

    Pozuelo-Rubio, M. Regulation of autophagic activity by 14-3-3zeta proteins associated with class III phosphatidylinositol-3-kinase. Cell Death Differ. 18, 479–492 (2011). This paper reports that 14-3-3ζ is a negative regulator of ceramide-induced autophagy through the regulation of a key component of early stages of the autophagy pathway.

    CAS  Google Scholar 

  141. 141

    Venable, M. E., Bielawska, A. & Obeid, L. M. Ceramide inhibits phospholipase D in a cell-free system. J. Biol. Chem. 271, 24800–24805 (1996).

    CAS  Google Scholar 

  142. 142

    Daido, S. et al. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res. 64, 4286–4293 (2004). This paper reports that ceramide induces autophagy via activation of BNIP3.

    CAS  Google Scholar 

  143. 143

    Mammucari, C. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458–471 (2007).

    CAS  PubMed  Google Scholar 

  144. 144

    Nath, K. A. The role of Sirt1 in renal rejuvenation and resistance to stress. J. Clin. Invest. 120, 1026–1028 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  145. 145

    Peralta, E. R. & Edinger, A. L. Ceramide-induced starvation triggers homeostatic autophagy. Autophagy 5, 407–409 (2009).

    CAS  Google Scholar 

  146. 146

    Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biol. 13, 132–141 (2011).

    CAS  Google Scholar 

  147. 147

    Sun, T. et al. c-Jun NH2-terminal kinase activation is essential for up-regulation of LC3 during ceramide-induced autophagy in human nasopharyngeal carcinoma cells. J. Transl. Med. 9, 161 (2011). This paper shows that the transcription factor JUN is involved in LC3 transcriptional regulation in response to ceramide.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. 148

    Pattingre, S. et al. Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy. J. Biol. Chem. 284, 2719–2728 (2009). This paper describes the potential role of JNK1 activation in ceramide-induced autophagy.

    CAS  PubMed Central  PubMed  Google Scholar 

  149. 149

    Li, D. D. et al. The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells. Oncogene 28, 886–898 (2009).

    CAS  Google Scholar 

  150. 150

    Park, M. A. et al. Regulation of autophagy by ceramide-CD95-PERK signaling. Autophagy 4, 929–931 (2008). This paper reports ceramide–CD95–PERK signalling as a novel pathway involved in autophagy.

    CAS  PubMed Central  PubMed  Google Scholar 

  151. 151

    Spassieva, S. D., Mullen, T. D., Townsend, D. M. & Obeid, L. M. Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response. Biochem. J. 424, 273–283 (2009). This paper reports a novel role of CERS2 in the induction of autophagy.

    CAS  PubMed Central  PubMed  Google Scholar 

  152. 152

    Tanabe, F., Cui, S. H. & Ito, M. Ceramide promotes calpain-mediated proteolysis of protein kinase C β in murine polymorphonuclear leukocytes. Biochem. Biophys. Res. Commun. 242, 129–133 (1998).

    CAS  Google Scholar 

  153. 153

    Xie, H. & Johnson, G. V. Ceramide selectively decreases tau levels in differentiated PC12 cells through modulation of calpain I. J. Neurochem. 69, 1020–1030 (1997).

    CAS  Google Scholar 

  154. 154

    Demarchi, F., Bertoli, C., Greer, P. A. & Schneider, C. Ceramide triggers an NF-κB-dependent survival pathway through calpain. Cell Death Differ. 12, 512–522 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  155. 155

    Demarchi, F. et al. Calpain is required for macroautophagy in mammalian cells. J. Cell Biol. 175, 595–605 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  156. 156

    Lepine, S., Allegood, J. C., Edmonds, Y., Milstien, S. & Spiegel, S. Autophagy induced by deficiency of sphingosine-1-phosphate phosphohydrolase 1 is switched to apoptosis by calpain-mediated autophagy-related gene 5 (Atg5) cleavage. J. Biol. Chem. 286, 44380–44390 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  157. 157

    Walker, T. et al. Sorafenib and vorinostat kill colon cancer cells by CD95-dependent and -independent mechanisms. Mol. Pharmacol. 76, 342–355 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  158. 158

    Zheng, W. et al. Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim. Biophys. Acta 1758, 1864–1884 (2006).

    CAS  Google Scholar 

  159. 159

    Wang, H., Maurer, B. J., Reynolds, C. P. & Cabot, M. C. N-(4-hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase. Cancer Res. 61, 5102–5105 (2001).

    CAS  Google Scholar 

  160. 160

    Rahmaniyan, M. et al. Identification of dihydroceramide desaturase as a direct in vitro target for fenretinide. J. Biol. Chem. 286, 24754–24764 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  161. 161

    Maurer, B. J., Metelitsa, L. S., Seeger, R. C., Cabot, M. C. & Reynolds, C. P. Increase of ceramide and induction of mixed apoptosis/necrosis by N-(4-hydroxyphenyl)- retinamide in neuroblastoma cell lines. J. Natl Cancer Inst. 91, 1138–1146 (1999).

    CAS  Google Scholar 

  162. 162

    Fazi, B. et al. Fenretinide induces autophagic cell death in caspase-defective breast cancer cells. Autophagy 4, 435–441 (2008).

    CAS  Google Scholar 

  163. 163

    Liu, X. W. et al. HIF-1α-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia. Pharmacol. Res. 62, 416–425 (2010).

    Google Scholar 

  164. 164

    Signorelli, P. et al. Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells. Cancer Lett. 282, 238–243 (2009).

    CAS  Google Scholar 

  165. 165

    Jiang, Q. et al. γ-tocotrienol induces apoptosis and autophagy in prostate cancer cells by increasing intracellular dihydrosphingosine and dihydroceramide. Int. J. Cancer 130, 685–693 (2012).

    CAS  Google Scholar 

  166. 166

    Kroemer, G. & Jaattela, M. Lysosomes and autophagy in cell death control. Nature Rev. Cancer 5, 886–897 (2005).

    CAS  Google Scholar 

  167. 167

    Separovic, D. et al. Increased ceramide accumulation correlates with downregulation of the autophagy protein ATG-7 in MCF-7 cells sensitized to photodamage. Arch. Biochem. Biophys. 494, 101–105 (2010).

    CAS  Google Scholar 

  168. 168

    Bhutia, S. K. et al. Autophagy switches to apoptosis in prostate cancer cells infected with melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). Autophagy 7, 1076–1077 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  169. 169

    Turner, L. S. et al. Autophagy is increased in prostate cancer cells overexpressing acid ceramidase and enhances resistance to C6 ceramide. Prostate Cancer Prostat. Dis. 14, 30–37 (2011).

    CAS  Google Scholar 

  170. 170

    Fujiwara, K. et al. Pivotal role of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 in apoptosis and autophagy. J. Biol. Chem. 283, 388–397 (2008).

    CAS  Google Scholar 

  171. 171

    Young, M. M. et al. Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J. Biol. Chem. 287, 12455–12468 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  172. 172

    Mirzoeva, O. K. et al. Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma. J. Mol. Med. 89, 877–889 (2011).

    CAS  Google Scholar 

  173. 173

    Thomas, S., Thurn, K. T., Bicaku, E., Marchion, D. C. & Munster, P. N. Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res. Treat. 130, 437–447 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  174. 174

    Han, W. et al. Autophagy inhibition enhances daunorubicin-induced apoptosis in K562 cells. PLoS ONE 6, e28491 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  175. 175

    Struckhoff, A. P., Patel, B. & Beckman, B. S. Inhibition of p53 sensitizes MCF-7 cells to ceramide treatment. Int. J. Oncol. 37, 21–30 (2010).

    CAS  Google Scholar 

  176. 176

    Wang, J., Lv, X. W., Shi, J. P. & Hu, X. S. Mechanisms involved in ceramide-induced cell cycle arrest in human hepatocarcinoma cells. World J. Gastroenterol. 13, 1129–1134 (2007). This paper reports the importance of PPARγ activation in ceramide-induced cell cycle arrest.

    CAS  PubMed Central  PubMed  Google Scholar 

  177. 177

    Lee, J. Y., Bielawska, A. E. & Obeid, L. M. Regulation of cyclin-dependent kinase 2 activity by ceramide. Exp. Cell Res. 261, 303–311 (2000). This paper revealed that ceramide regulates CDK2 through p21 and protein phosphatases to induce cell cycle arrest.

    CAS  Google Scholar 

  178. 178

    Kim, W. H., Kang, K. H., Kim, M. Y. & Choi, K. H. Induction of p53-independent p21 during ceramide-induced G1 arrest in human hepatocarcinoma cells. Biochem. Cell Biol. 78, 127–135 (2000).

    CAS  Google Scholar 

  179. 179

    Alesse, E. et al. The growth arrest and downregulation of c-myc transcription induced by ceramide are related events dependent on p21 induction, Rb underphosphorylation and E2F sequestering. Cell Death Differ. 5, 381–389 (1998).

    CAS  Google Scholar 

  180. 180

    Han, C. et al. PPARγ ligands inhibit cholangiocarcinoma cell growth through p53-dependent GADD45 and p21 pathway. Hepatology 38, 167–177 (2003).

    Google Scholar 

  181. 181

    Kraveka, J. M. et al. Involvement of dihydroceramide desaturase in cell cycle progression in human neuroblastoma cells. J. Biol. Chem. 282, 16718–16728 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  182. 182

    Clarke, C. J. et al. Neutral sphingomyelinase-2 mediates growth arrest by retinoic acid through modulation of ribosomal S6 kinase. J. Biol. Chem. 286, 21565–21576 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  183. 183

    Zhu, X. F., Liu, Z. C., Xie, B. F., Feng, G. K. & Zeng, Y. X. Ceramide induces cell cycle arrest and upregulates p27kip in nasopharyngeal carcinoma cells. Cancer Lett. 193, 149–154 (2003).

    CAS  Google Scholar 

  184. 184

    Phillips, D. C. et al. Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression. Cell Death Differ. 14, 1780–1791 (2007).

    CAS  Google Scholar 

  185. 185

    Lechler, P. et al. The antiapoptotic gene survivin is highly expressed in human chondrosarcoma and promotes drug resistance in chondrosarcoma cells in vitro. BMC Cancer 11, 120 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  186. 186

    Ahn, E. H. & Schroeder, J. J. Induction of apoptosis by sphingosine, sphinganine, and C2-ceramide in human colon cancer cells, but not by C2-dihydroceramide. Anticancer Res. 30, 2881–2884 (2010).

    CAS  Google Scholar 

  187. 187

    Tsaur, I. et al. The cdk1-cyclin B complex is involved in everolimus triggered resistance in the PC3 prostate cancer cell line. Cancer Lett. 313, 84–90 (2011).

    CAS  Google Scholar 

  188. 188

    Scaltriti, M. et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc. Natl Acad. Sci. USA 108, 3761–3766 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  189. 189

    Zwart, W. et al. Resistance to antiestrogen arzoxifene is mediated by overexpression of cyclin D1. Mol. Endocrinol. 23, 1335–1345 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  190. 190

    Obama, K., Kanai, M., Kawai, Y., Fukushima, M. & Takabayashi, A. Role of retinoblastoma protein and E2F-1 transcription factor in the acquisition of 5-fluorouracil resistance by colon cancer cells. Int. J. Oncol. 21, 309–314 (2002).

    CAS  Google Scholar 

  191. 191

    Kolesnick, R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J. Clin. Invest. 110, 3–8 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  192. 192

    Ogretmen, B. & Hannun, Y. A. Biologically active sphingolipids in cancer pathogenesis and treatment. Nature Rev. Cancer 4, 604–616 (2004).

    CAS  Google Scholar 

  193. 193

    Barth, B. M., Cabot, M. C. & Kester, M. Ceramide-based therapeutics for the treatment of cancer. Anticancer Agents Med. Chem. 11, 911–919 (2011).

    CAS  Google Scholar 

  194. 194

    Haimovitz-Friedman, A. et al. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J. Exp. Med. 180, 525–535 (1994).

    CAS  Google Scholar 

  195. 195

    Santana, P. et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 86, 189–199 (1996).

    CAS  Google Scholar 

  196. 196

    Silva, L. C. et al. Ablation of ceramide synthase 2 strongly affects biophysical properties of membranes. J. Lipid Res. 53, 430–436 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  197. 197

    Pewzner-Jung, Y. et al. A critical role for ceramide synthase 2 in liver homeostasis: II. insights into molecular changes leading to hepatopathy. J. Biol. Chem. 285, 10911–10923 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  198. 198

    Kohno, M. et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol. Cell. Biol. 26, 7211–7223 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  199. 199

    Kawamori, T. et al. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 23, 405–414 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  200. 200

    Kummar, S. et al. Phase I trial of fenretinide lym-x-sorb oral powder in adults with solid tumors and lymphomas. Anticancer Res. 31, 961–966 (2011).

    CAS  Google Scholar 

  201. 201

    Villablanca, J. G. et al. Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children's Oncology Group. Clin. Cancer Res. 17, 6858–6866 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  202. 202

    Tran, M. A., Smith, C. D., Kester, M. & Robertson, G. P. Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development. Clin. Cancer Res. 14, 3571–3581 (2008).

    CAS  Google Scholar 

  203. 203

    Stover, T. C., Sharma, A., Robertson, G. P. & Kester, M. Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin. Cancer Res. 11, 3465–3474 (2005).

    CAS  Google Scholar 

  204. 204

    Morad, S. A. F. et al. Tamoxifen enhances chemotherapeutic efficacy of C6− ceramide and increases induction of apoptosis in human colorectal cancer cells by upregulation of MAPK signaling pathway and down-regulation of inhibitor of apoptosis protein, survivin. FASEB J. 26, 993.1 (2012).

    Google Scholar 

  205. 205

    Kornhuber, J. et al. Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications. Cell. Physiol. Biochem. 26, 9–20 (2010).

    CAS  Google Scholar 

  206. 206

    Smith, E. L. & Schuchman, E. H. The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. FASEB J. 22, 3419–3431 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  207. 207

    Ling, L. U., Lin, H., Tan, K. B. & Chiu, G. N. The role of protein kinase C in the synergistic interaction of safingol and irinotecan in colon cancer cells. Int. J. Oncol. 35, 1463–1471 (2009).

    CAS  Google Scholar 

  208. 208

    Ling, L. U., Tan, K. B. & Chiu, G. N. Role of reactive oxygen species in the synergistic cytotoxicity of safingol-based combination regimens with conventional chemotherapeutics. Oncol. Lett. 2, 905–910 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  209. 209

    Coward, J. et al. Safingol (L-threo-sphinganine) induces autophagy in solid tumor cells through inhibition of PKC and the PI3-kinase pathway. Autophagy 5, 184–193 (2009).

    CAS  Google Scholar 

  210. 210

    Dickson, M. A. et al. A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors. Clin. Cancer Res. 17, 2484–2492 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

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Supported in part through grants from the US National Institutes of Health (GM77391, CA143755), and funding from the Fashion Footwear Association of New York Charitable Foundation (New York, USA) and the Associates for Breast and Prostate Cancer Studies (Los Angeles, USA).

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Correspondence to Samy A. F. Morad or Myles C. Cabot.

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The authors declare no competing financial interests.

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Supplementary information

Supplementary information S1

Sphingolipid enzymes that are altered in cancer (PDF 96 kb)

Supplementary information S2

Inhibitors of ceramide metabolism to enhance therapeutic potential of anticancer agents (PDF 126 kb)



A class of membrane lipids that includes sphingomyelin, which contains an 18-carbon monounsaturated amino alcohol moiety, sphingosine.


The neutral lipid backbone of complex sphingolipids, including glycolipids, which consists of a long-chain amino alcohol, sphingosine, linked to a fatty acid via an amide bond.

Serine palmitoyltransferase

The enzyme that catalyses the first step in the biosynthesis of sphingolipids, the condensation of serine and palmitoyl-CoA.


Enzymes catalysing hydrolysis of the fatty acid moiety of ceramide, producing sphingosine.


(SMase). A hydrolase that breaks down sphingomyelin into ceramide and the polar headgroup phosphocholine.

Glucosylceramide synthase

(GCS). Also known as ceramide glucosyltransferase. Catalyses the transfer of UDP-glucose to ceramide to form glucosylceramide, a reaction often used by cancer cells to detoxify ceramide.

Sphingomyelin synthases

(SMSs). The enzymes responsible for the synthesis of sphingomyelin, which use ceramide and phosphatidylcholine (lecithin) as substrates.


A class of antitumour (antimitotic or antimicrotubule) agents derived from Taxus brevifolia (the Pacific yew tree); examples include paclitaxel and docetaxel.

DNA crosslinking agent

Chemicals that bind to strands of DNA that block DNA replication, resulting in DNA replication arrest and tumour cell death. For example, chemotherapeutic agents such as carmustine and nitrogen mustard.

Ceramide-enriched membrane platforms

Ceramide-enriched regions of the plasma membrane that have distinct structural composition that function as platforms to colocalize proteins involved in intracellular signalling.

Inhibitor of apoptosis protein (IAP) family

A family of proteins that function as endogenous inhibitors of apoptosis. These proteins can bind to caspases (executioner proteins) thereby preventing apoptosis.


A process that removes damaged mitochondria from the cell before leading to cell death (mitochondrial autophagy).

BH3-only family

Members of the BCL-2 pro-apoptotic protein family essential for initiating apoptosis.

Short-chain ceramides

Ceramide analogues consisting of sphingosine linked by an amide bond to a short-chain fatty acid, such as hexanoic acid (6 carbons), and are often used because they are cell-permeable and mimic the effects of natural ceramides.


The digestive vacuole of autophagy that is generated by the fusion of lysosome and autophagic vacuole.


Enzymes that catalyse hydrolytic cleavage of peptide bonds in proteins leading to protein degradation.

Triple-negative breast cancer

A heterogenous group of breast cancers that do not express oestrogen receptor, progesterone receptor and HER2, and are thus refractory to endocrine therapy such as tamoxifen and trastuzumab.

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Morad, S., Cabot, M. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 13, 51–65 (2013).

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