Advertisement

Clinical application of ceramide in cancer treatment

  • Kazuki Moro
  • Masayuki NagahashiEmail author
  • Emmanuel Gabriel
  • Kazuaki Takabe
  • Toshifumi Wakai
Review Article
  • 65 Downloads

Abstract

Development of innovative strategies for cancer treatment is a pressing public health issue. Despite recent advances, the mechanisms of cancer progression and the resistance to cancer treatment have not been fully elucidated. Sphingolipids, including ceramide and sphingoshin-1-phosphate, are bioactive mediators that regulate cancer cell death and survival through the dynamic balance of what has been termed the ‘sphingolipid rheostat’. Specifically, ceramide, which acts as the central hub of sphingolipid metabolism, is generated via three major pathways by many stressors, including anti-cancer treatments, environmental stresses, and cytokines. We have previously shown in breast cancer patients that elevated ceramide correlated with less aggressive cancer phenotypes, leading to a prognostic impact. Recent studies showed that ceramide have the possibility of becoming the reinforcing agent of cancer treatment as well as other roles such as nanoparticles and diagnostic biomarker. We review ceramide as one of the key molecules to investigate in overcoming resistance to current drug therapies and in becoming one of the newest cancer treatments.

Keywords

Apoptosis Cancer Ceramide Drug resistance Sphingosine-1-phosphate 

Notes

Acknowledgements

This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research Grant Number 18K19576 for MN, and 16K15610 for TW. MN was supported by the Uehara Memorial Foundation, Takeda Science Foundation, and Tsukada Medical Foundation. KT was supported by NIH/NCI grant R01CA160688 and Susan G. Komen Investigator Initiated Research Grant IIR12222224.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.CrossRefGoogle Scholar
  2. 2.
    Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 2014;14:535–46.CrossRefGoogle Scholar
  3. 3.
    Hartwell LH, Kastan MB. Cell cycle control and cancer. Science. 1994;266:1821–8.CrossRefGoogle Scholar
  4. 4.
    Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 1999;286:1358–62.CrossRefGoogle Scholar
  5. 5.
    Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001;27:247–54.CrossRefGoogle Scholar
  6. 6.
    Sotomayor EM, Borrello I, Levitsky HI. Tolerance and cancer: a critical issue in tumor immunology. Crit Rev Oncog. 1996;7:433–56.CrossRefGoogle Scholar
  7. 7.
    Hannun YA, Obeid LM. The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem. 2002;277:25847–50.CrossRefGoogle Scholar
  8. 8.
    Spiegel S, Cuvillier O, Edsall L, Kohama T, Menzeleev R, Olivera A, et al. Roles of sphingosine-1-phosphate in cell growth, differentiation, and death. Biochemistry. 1998;63:69–73.Google Scholar
  9. 9.
    Newton J, Lima S, Maceyka M, Spiegel S. Revisiting the sphingolipid rheostat: evolving concepts in cancer therapy. Exp Cell Res. 2015;333:195–200.CrossRefGoogle Scholar
  10. 10.
    Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind S, et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 1996;381:800–3.CrossRefGoogle Scholar
  11. 11.
    Obeid LM, Linardic CM, Karolak LA, Hannun YA. Programmed cell death induced by ceramide. Science. 1993;259:1769–71.CrossRefGoogle Scholar
  12. 12.
    Nagahashi M, Ramachandran S, Kim EY, Allegood JC, Rashid OM, Yamada A, et al. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res. 2012;72:726–35.CrossRefGoogle Scholar
  13. 13.
    Salas A, Ponnusamy S, Senkal CE, Meyers-Needham M, Selvam SP, Saddoughi SA, 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;117:5941–52.CrossRefGoogle Scholar
  14. 14.
    Young MM, Kester M, Wang HG. Sphingolipids: regulators of crosstalk between apoptosis and autophagy. J Lipid Res. 2013;54:5–19.CrossRefGoogle Scholar
  15. 15.
    Hannun YA, Obeid LM. Many ceramides. J Biol Chem. 2011;286:27855–62.CrossRefGoogle Scholar
  16. 16.
    Kitatani K, Idkowiak-Baldys J, Hannun YA. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal. 2008;20:1010–8.CrossRefGoogle Scholar
  17. 17.
    Grassme H, Jekle A, Riehle A, Schwarz H, Berger J, Sandhoff K, et al. CD95 signaling via ceramide-rich membrane rafts. J Biol Chem. 2001;276:20589–96.CrossRefGoogle Scholar
  18. 18.
    Colombini M. Membrane channels formed by ceramide. In: Gulbins E, Petrache I, editors. Sphingolipids: basic science and drug development. Vienna: Springer; 2013. p. 109–26.CrossRefGoogle Scholar
  19. 19.
    Garcia-Gonzalez V, Diaz-Villanueva JF, Galindo-Hernandez O, Martinez-Navarro I, Hurtado-Ureta G, Perez-Arias AA. Ceramide metabolism balance, a multifaceted factor in critical steps of breast cancer development. Int J Mol Sci. 2018;19:2527.CrossRefGoogle Scholar
  20. 20.
    Pewzner-Jung Y, Park H, Laviad EL, Silva LC, Lahiri S, Stiban J, et al. A critical role for ceramide synthase 2 in liver homeostasis: I. alterations in lipid metabolic pathways. J Biol Chem. 2010;285:10902–10.CrossRefGoogle Scholar
  21. 21.
    Mao Z, Sun W, Xu R, Novgorodov S, Szulc ZM, Bielawski J, et al. Alkaline ceramidase 2 (ACER2) and its product dihydrosphingosine mediate the cytotoxicity of N-(4-hydroxyphenyl)retinamide in tumor cells. J Biol Chem. 2010;285:29078–90.CrossRefGoogle Scholar
  22. 22.
    Ledesma MD, Prinetti A, Sonnino S, Schuchman EH. Brain pathology in Niemann Pick disease type A: insights from the acid sphingomyelinase knockout mice. J Neurochem. 2011;116:779–88.CrossRefGoogle Scholar
  23. 23.
    Casasampere M, Ordonez YF, Casas J, Fabrias G. Dihydroceramide desaturase inhibitors induce autophagy via dihydroceramide-dependent and independent mechanisms. Biochim Biophys Acta. 2017;1861:264–75.CrossRefGoogle Scholar
  24. 24.
    Lee AY, Lee JW, Kim JE, Mock HJ, Park S, Kim S, et al. Dihydroceramide is a key metabolite that regulates autophagy and promotes fibrosis in hepatic steatosis model. Biochem Biophys Res Commun. 2017;494:460–9.CrossRefGoogle Scholar
  25. 25.
    Hillig I, Leipelt M, Ott C, Zahringer U, Warnecke D, Heinz E. Formation of glucosylceramide and sterol glucoside by a UDP-glucose-dependent glucosylceramide synthase from cotton expressed in Pichia pastoris. FEBS Lett. 2003;553:365–9.CrossRefGoogle Scholar
  26. 26.
    Liu YY, Patwardhan GA, Xie P, Gu X, Giuliano AE, Cabot MC. Glucosylceramide synthase, a factor in modulating drug resistance, is overexpressed in metastatic breast carcinoma. Int J Oncol. 2011;39:425–31.Google Scholar
  27. 27.
    Liu YY, Patwardhan GA, Bhinge K, Gupta V, Gu X, Jazwinski SM. Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells. Cancer Res. 2011;71:2276–85.CrossRefGoogle Scholar
  28. 28.
    Pena LA, Fuks Z, Kolesnick R. Stress-induced apoptosis and the sphingomyelin pathway. Biochem Pharmacol. 1997;53:615–21.CrossRefGoogle Scholar
  29. 29.
    Hertervig E, Nilsson A, Nyberg L, Duan RD. Alkaline sphingomyelinase activity is decreased in human colorectal carcinoma. Cancer. 1997;79:448–53.CrossRefGoogle Scholar
  30. 30.
    Senkal CE, Ponnusamy S, Bielawski J, Hannun YA, 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. 2010;24:296–308.CrossRefGoogle Scholar
  31. 31.
    Coroneos E, Wang Y, Panuska JR, Templeton DJ, Kester M. Sphingolipid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades. Biochem J. 1996;316(Pt 1):13–7.CrossRefGoogle Scholar
  32. 32.
    Hartmann D, Lucks J, Fuchs S, Schiffmann S, Schreiber Y, Ferreiros N, et al. Long chain ceramides and very long chain ceramides have opposite effects on human breast and colon cancer cell growth. Int J Biochem Cell Biol. 2012;44:620–8.CrossRefGoogle Scholar
  33. 33.
    Ruckhaberle E, Holtrich U, Engels K, Hanker L, Gatje R, Metzler D, et al. Acid ceramidase 1 expression correlates with a better prognosis in ER-positive breast cancer. Climacteric. 2009;12:502–13.CrossRefGoogle Scholar
  34. 34.
    Saad AF, Meacham WD, Bai A, Anelli V, Elojeimy S, Mahdy AE, et al. The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy. Cancer Biol Ther. 2007;6:1455–60.CrossRefGoogle Scholar
  35. 35.
    Takabe K, Paugh SW, Milstien S, Spiegel S. “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev. 2008;60:181–95.CrossRefGoogle Scholar
  36. 36.
    Tsuchida J, Nagahashi M, Takabe K, Wakai T. Clinical Impact of Sphingosine-1-Phosphate in Breast Cancer. Mediators Inflamm. 2017;2017:2076239.CrossRefGoogle Scholar
  37. 37.
    Nagahashi M, Takabe K, Liu R, Peng K, Wang X, Wang Y, et al. Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology. 2015;61:1216–26.CrossRefGoogle Scholar
  38. 38.
    Young N, Pearl DK, Van Brocklyn JR. Sphingosine-1-phosphate regulates glioblastoma cell invasiveness through the urokinase plasminogen activator system and CCN1/Cyr61. Mol Cancer Res. 2009;7:23–32.CrossRefGoogle Scholar
  39. 39.
    Kawamori T, Osta W, Johnson KR, Pettus BJ, Bielawski J, Tanaka T, et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. Faseb J. 2006;20:386–8.CrossRefGoogle Scholar
  40. 40.
    Fyrst H, Saba JD. Sphingosine-1-phosphate lyase in development and disease: sphingolipid metabolism takes flight. Biochim Biophys Acta. 2008;1781:448–58.CrossRefGoogle Scholar
  41. 41.
    Min J, Van Veldhoven PP, Zhang L, Hanigan MH, Alexander H, Alexander S. Sphingosine-1-phosphate lyase regulates sensitivity of human cells to select chemotherapy drugs in a p38-dependent manner. Mol Cancer Res. 2005;3:287–96.CrossRefGoogle Scholar
  42. 42.
    Brizuela L, Ader I, Mazerolles C, Bocquet M, Malavaud B, Cuvillier O. First evidence of sphingosine 1-phosphate lyase protein expression and activity downregulation in human neoplasm: implication for resistance to therapeutics in prostate cancer. Mol Cancer Ther. 2012;11:1841–51.CrossRefGoogle Scholar
  43. 43.
    Wrage M, Ruosaari S, Eijk PP, Kaifi JT, Hollmen J, Yekebas EF, et al. Genomic profiles associated with early micrometastasis in lung cancer: relevance of 4q deletion. Clin Cancer Res. 2009;15:1566–74.CrossRefGoogle Scholar
  44. 44.
    Arana L, Gangoiti P, Ouro A, Trueba M, Gomez-Munoz A. Ceramide and ceramide 1-phosphate in health and disease. Lipids Health Dis. 2010;9:15.CrossRefGoogle Scholar
  45. 45.
    Zeidan YH, Jenkins RW, Hannun YA. Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway. J Cell Biol. 2008;181:335–50.CrossRefGoogle Scholar
  46. 46.
    Yang L, Zheng LY, Tian Y, Zhang ZQ, Dong WL, Wang XF, et al. C6 ceramide dramatically enhances docetaxel-induced growth inhibition and apoptosis in cultured breast cancer cells: a mechanism study. Exp Cell Res. 2015;332:47–59.CrossRefGoogle Scholar
  47. 47.
    Molteni LP, Rampinelli I, Cergnul M, Scaglietti U, Paino AM, Noonan DM, et al. Capecitabine in breast cancer: the issue of cardiotoxicity during fluoropyrimidine treatment. Breast J. 2010;16(Suppl 1):45-8.Google Scholar
  48. 48.
    Modrak DE, Rodriguez MD, Goldenberg DM, Lew W, Blumenthal RD. Sphingomyelin enhances chemotherapy efficacy and increases apoptosis in human colonic tumor xenografts. Int J Oncol. 2002;20:379–84.Google Scholar
  49. 49.
    Eichhorst ST, Muerkoster S, Weigand MA, Krammer PH. The chemotherapeutic drug 5-fluorouracil induces apoptosis in mouse thymocytes in vivo via activation of the CD95(APO-1/Fas) system. Cancer Res. 2001;61:243–8.Google Scholar
  50. 50.
    Ilson DH, Saltz L, Enzinger P, Huang Y, Kornblith A, Gollub M, et al. Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol. 1999;17:3270–5.CrossRefGoogle Scholar
  51. 51.
    Moro K, Nagahashi M, Naito T, Nagai Y, Katada T, Minagawa M, et al. Gastric adenosquamous carcinoma producing granulocyte-colony stimulating factor: a case of a rare malignancy. Surg Case Rep. 2017;3:67.CrossRefGoogle Scholar
  52. 52.
    Denkert C, Liedtke C, Tutt A, von Minckwitz G. Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet. 2017;389:2430–42.CrossRefGoogle Scholar
  53. 53.
    Noda S, Yoshimura S, Sawada M, Naganawa T, Iwama T, Nakashima S, et al. Role of ceramide during cisplatin-induced apoptosis in C6 glioma cells. J Neurooncol. 2001;52:11–21.CrossRefGoogle Scholar
  54. 54.
    Sassa T, Suto S, Okayasu Y, Kihara A. A shift in sphingolipid composition from C24 to C16 increases susceptibility to apoptosis in HeLa cells. Biochim Biophys Acta. 2012;1821:1031–7.CrossRefGoogle Scholar
  55. 55.
    Lacour S, Hammann A, Grazide S, Lagadic-Gossmann D, Athias A, Sergent O, et al. Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. Cancer Res. 2004;64:3593–8.CrossRefGoogle Scholar
  56. 56.
    Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27.CrossRefGoogle Scholar
  57. 57.
    Patel NR, Pattni BS, Abouzeid AH, Torchilin VP. Nanopreparations to overcome multidrug resistance in cancer. Adv Drug Deliv Rev. 2013;65:1748–62.CrossRefGoogle Scholar
  58. 58.
    Chang JE, Cho HJ, Yi E, Kim DD, Jheon S. Hypocrellin B and paclitaxel-encapsulated hyaluronic acid-ceramide nanoparticles for targeted photodynamic therapy in lung cancer. J Photochem Photobiol B. 2016;158:113–21.CrossRefGoogle Scholar
  59. 59.
    Deshpande D, Devalapally H, Amiji M. Enhancement in anti-proliferative effects of paclitaxel in aortic smooth muscle cells upon co-administration with ceramide using biodegradable polymeric nanoparticles. Pharm Res. 2008;25:1936–47.CrossRefGoogle Scholar
  60. 60.
    Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7:a020412.CrossRefGoogle Scholar
  61. 61.
    Cipriani R, Chara JC, Rodriguez-Antiguedad A, Matute C. FTY720 attenuates excitotoxicity and neuroinflammation. J Neuroinflamm. 2015;12:86.CrossRefGoogle Scholar
  62. 62.
    Mesev EV, Miller DS, Cannon RE. Ceramide 1-Phosphate Increases P-Glycoprotein Transport Activity at the Blood-Brain Barrier via Prostaglandin E2 Signaling. Mol Pharmacol. 2017;91:373–82.CrossRefGoogle Scholar
  63. 63.
    Doan NB, Alhajala H, Al-Gizawiy MM, Mueller WM, Rand SD, Connelly JM, et al. Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency. Oncotarget. 2017;8:112662–74.Google Scholar
  64. 64.
    Che J, Huang Y, Xu C, Zhang P. Increased ceramide production sensitizes breast cancer cell response to chemotherapy. Cancer Chemother Pharmacol. 2017;79:933–41.CrossRefGoogle Scholar
  65. 65.
    Morad SA, Cabot MC. Tamoxifen regulation of sphingolipid metabolism—therapeutic implications. Biochim Biophys Acta. 2015;1851:1134–45.CrossRefGoogle Scholar
  66. 66.
    Morad SA, Ryan TE, Neufer PD, Zeczycki TN, Davis TS, MacDougall MR, et al. Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia. J Lipid Res. 2016;57:1231–42.CrossRefGoogle Scholar
  67. 67.
    Morad SA, Levin JC, Shanmugavelandy SS, Kester M, Fabrias G, Bedia C, et al. Ceramide—antiestrogen nanoliposomal combinations—novel impact of hormonal therapy in hormone-insensitive breast cancer. Mol Cancer Ther. 2012;11:2352–61.CrossRefGoogle Scholar
  68. 68.
    Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004;6:553–63.Google Scholar
  69. 69.
    Fisher B, Bauer M, Margolese R, Poisson R, Pilch Y, Redmond C, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med. 1985;312:665–73.CrossRefGoogle Scholar
  70. 70.
    Linkous AG, Yazlovitskaya EM. Novel radiosensitizing anticancer therapeutics. Anticancer Res. 2012;32:2487–99.Google Scholar
  71. 71.
    Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155–9.CrossRefGoogle Scholar
  72. 72.
    Mesicek J, Lee H, Feldman T, Jiang X, Skobeleva A, Berdyshev EV, et al. Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells. Cell Signal. 2010;22:1300–7.CrossRefGoogle Scholar
  73. 73.
    Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 2002;99:12293–7.CrossRefGoogle Scholar
  74. 74.
    Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagita H, et al. PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells. J Immunol. 2009;182:2816–26.CrossRefGoogle Scholar
  75. 75.
    Nagahashi M, Tsuchida J, Moro K, Hasegawa M, Tatsuda K, Woelfel IA, et al. High levels of sphingolipids in human breast cancer. J Surg Res. 2016;204:435–44.CrossRefGoogle Scholar
  76. 76.
    Moro K, Kawaguchi T, Tsuchida J, Gabriel E, Qi Q, Yan L, et al. Ceramide species are elevated in human breast cancer and are associated with less aggressiveness. Oncotarget. 2018;9:19874–90.CrossRefGoogle Scholar
  77. 77.
    Tsuchida J, Nagahashi M, Nakajima M, Moro K, Tatsuda K, Ramanathan R, et al. Breast cancer sphingosine-1-phosphate is associated with phospho-sphingosine kinase 1 and lymphatic metastasis. J Surg Res. 2016;205:85–94.CrossRefGoogle Scholar
  78. 78.
    Jatoi A, Suman VJ, Schaefer P, Block M, Loprinzi C, Roche P, et al. A phase II study of topical ceramides for cutaneous breast cancer. Breast Cancer Res Treat. 2003;80:99–104.CrossRefGoogle Scholar
  79. 79.
    Hon KL, Pong NH, Wang SS, Lee VW, Luk NM, Leung TF. Acceptability and efficacy of an emollient containing ceramide-precursor lipids and moisturizing factors for atopic dermatitis in pediatric patients. Drugs R D. 2013;13:37–42.CrossRefGoogle Scholar
  80. 80.
    Grammatikos G, Schoell N, Ferreiros N, Bon D, Herrmann E, Farnik H, et al. Serum sphingolipidomic analyses reveal an upregulation of C16-ceramide and sphingosine-1-phosphate in hepatocellular carcinoma. Oncotarget. 2016;7:18095–105.CrossRefGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2019

Authors and Affiliations

  1. 1.Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental SciencesNiigata CityJapan
  2. 2.Department of SurgeryMayo ClinicJacksonvilleUSA
  3. 3.Division of Breast Surgery, Department of Surgical OncologyRoswell Park Comprehensive Cancer CenterBuffaloUSA
  4. 4.Department of Surgery, Jacobs School of Medicine and Biomedical SciencesUniversity at Buffalo, the State University of New YorkBuffaloUSA

Personalised recommendations