Skip to main content
SpringerLink
Log in
Book cover

Bioactive Sphingolipids in Cancer Biology and Therapy pp 211–233Cite as

Pancreatic Cancer and Sphingolipids

  • Chapter

  • 857 Accesses

Abstract

Sphingolipid metabolism is an area of cancer science that has recently risen to prominence in the laboratory and in the clinical arena. This is because ceramide, the aliphatic backbone of sphingolipids, can act as a powerful tumor censor; a favorable attribute. However, cancer cells are equipped to efficiently inactivate ceramide via various metabolic routes: glycosylation to form glucosylceramide, and hydrolysis, which generates sphingosine and then, through the action of sphingosine kinase, sphingosine 1-phosphate, a tumor cell mitogen. These actions severely blunt ceramide anticancer properties, thwarting potential utility in treatment, and pancreatic cancer, a drug resistant, severely aggressive malignancy, is no exception. In this chapter we will review pancreatic cancer epidemiology, classical treatment options, and progression, and survey sphingolipid metabolism in pancreatic cancer as it relates to the action and efficacy of anticancer drugs. The work will conclude with ideas on how targeting ceramide metabolism could reveal new vulnerabilities for countering growth of this intractable malignancy.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Bigsby J (1835) Observations, pathological and therapeutic, on diseases of the pancreas. Edinburgh Med Surg J 44:85–102

    Google Scholar 

  2. Da Costa JM (1858) Cancer of the pancreas. North Am Med Chir Rev 2:883

    Google Scholar 

  3. Baskova IP, Iusupova GI, Nikonov GI (1984) [Lipase and cholesterol-esterase activity in the salivary gland secretions of the medical leech Hirudo medicinalis]. Biokhimiia 49(4):676–678

    CAS  PubMed  Google Scholar 

  4. Rabinowitz JL (1996) Salivary lipid profiles of the leech (Hirudo medicinalis). Lipids 31(8):887–888

    Article  CAS  PubMed  Google Scholar 

  5. Whipple AO, Parsons WB, Mullins CR (1935) Treatment of carcinoma of the ampulla of Vater. Ann Surg 102(4):763–779

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Brunschwig A (1937) Resection of head of pancreas and duodenum for carcinoma—pancreatoduodenectomy. Surg Gynecol Obstet 65:681–684

    Google Scholar 

  7. Silverman DT, Hoover RN, Brown LM, Swanson GM, Schiffman M, Greenberg RS et al (2003) Why do Black Americans have a higher risk of pancreatic cancer than White Americans? Epidemiology 14(1):45–54

    Article  PubMed  Google Scholar 

  8. Arslan AA, Helzlsouer KJ, Kooperberg C, Shu XO, Steplowski E, Bueno-de-Mesquita HB et al (2010) Anthropometric measures, body mass index, and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Arch Intern Med 170(9):791–802

    Article  PubMed Central  PubMed  Google Scholar 

  9. Mohr SB, Garland CF, Gorham ED, Grant WB, Garland FC (2010) Ultraviolet B irradiance and vitamin D status are inversely associated with incidence rates of pancreatic cancer worldwide. Pancreas 39(5):669–674

    Article  CAS  PubMed  Google Scholar 

  10. Bao Y, Ng K, Wolpin BM, Michaud DS, Giovannucci E, Fuchs CS (2010) Predicted vitamin D status and pancreatic cancer risk in two prospective cohort studies. Br J Cancer 102(9):1422–1427

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Fitz RH (1889) Acute pancreatitis: a consideration of pancreatic hemorrhage, hemorrhagic, suppurative, and gangrenous pancreatitis, and of disseminated fat-necrosis. Boston Med Surg J 120(8):181–187, 205–207, 29–35

    Google Scholar 

  12. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR et al (1993) Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 328(20):1433–1437

    Article  CAS  PubMed  Google Scholar 

  13. Chiari H (1896) Über die Selbstverdauung des menschlichen Pankreas. Z Heilk 17:69–96

    Google Scholar 

  14. Opie EL (1901) The etiology of acute hemorrhagic pancreatitis. Johns Hopkins Hosp Bull 12:182–188

    Google Scholar 

  15. Comfort MW, Gambill EE, Baggenstoss AH (1946) Chronic relapsing pancreatitis; a study of 29 cases without associated disease of the biliary or gastrointestinal tract. Gastroenterology 6:376–408

    CAS  PubMed  Google Scholar 

  16. Vonlaufen A, Spahr L, Apte MV, Frossard JL (2014) Alcoholic pancreatitis: a tale of spirits and bacteria. World J Gastrointest Pathophysiol 5(2):82–90

    PubMed Central  PubMed  Google Scholar 

  17. Ling S, Feng T, Jia K, Tian Y, Li Y (2014) Inflammation to cancer: the molecular biology in the pancreas (Review). Oncol Lett 7(6):1747–1754

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Ekbom A, McLaughlin JK, Karlsson BM, Nyren O, Gridley G, Adami HO et al (1994) Pancreatitis and pancreatic cancer: a population-based study. J Natl Cancer Inst 86(8):625–627

    Article  CAS  PubMed  Google Scholar 

  19. Talamini G, Falconi M, Bassi C, Sartori N, Salvia R, Caldiron E et al (1999) Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol 94(5):1253–1260

    Article  CAS  PubMed  Google Scholar 

  20. Bracci PM, Wang F, Hassan MM, Gupta S, Li D, Holly EA (2009) Pancreatitis and pancreatic cancer in two large pooled case-control studies. Cancer Causes Control 20(9):1723–1731

    Article  PubMed Central  PubMed  Google Scholar 

  21. Morad SA, Cabot MC (2013) Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 13(1):51–65

    Article  CAS  PubMed  Google Scholar 

  22. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413

    CAS  PubMed  Google Scholar 

  23. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825

    Article  CAS  PubMed  Google Scholar 

  24. Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE et al (2011) Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 29(34):4548–4554

    Article  CAS  Google Scholar 

  25. Senchenkov A, Litvak DA, Cabot MC (2001) Targeting ceramide metabolism–a strategy for overcoming drug resistance. J Natl Cancer Inst 93(5):347–357

    Article  CAS  PubMed  Google Scholar 

  26. Barth BM, Cabot MC, Kester M (2011) Ceramide-based therapeutics for the treatment of cancer. Anticancer Agents Med Chem 11(9):911–919

    Article  CAS  PubMed  Google Scholar 

  27. Gouaze-Andersson V, Cabot MC (2011) Sphingolipid metabolism and drug resistance in hematological malignancies. Anticancer Agents Med Chem 11(9):891–903

    Article  CAS  PubMed  Google Scholar 

  28. Liu J, Beckman BS, Foroozesh M (2013) A review of ceramide analogs as potential anticancer agents. Future Med Chem 5(12):1405–1421

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Saddoughi SA, Ogretmen B (2013) Diverse functions of ceramide in cancer cell death and proliferation. Adv Cancer Res 117:37–58

    Article  CAS  PubMed  Google Scholar 

  30. Dimanche-Boitrel MT, Rebillard A, Gulbins E (2011) Ceramide in chemotherapy of tumors. Recent Pat Anticancer Drug Discov 6(3):284–293

    Article  CAS  PubMed  Google Scholar 

  31. Stover TC, Sharma A, Robertson GP, Kester M (2005) Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin Cancer Res 11(9):3465–3474

    Article  CAS  PubMed  Google Scholar 

  32. Tran MA, Smith CD, Kester M, Robertson GP (2008) Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development. Clin Cancer Res 14(11):3571–3581

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Jiang Y, DiVittore NA, Kaiser JM, Shanmugavelandy SS, Fritz JL, Heakal Y et al (2011) Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer Biol Ther 12(7):574–585

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Ravindranath MH, Gonzales AM, Nishimoto K, Tam WY, Soh D, Morton DL (2000) Immunology of gangliosides. Indian J Exp Biol 38(4):301–312

    CAS  PubMed  Google Scholar 

  37. Fredman P, Hedberg K, Brezicka T (2003) Gangliosides as therapeutic targets for cancer. BioDrugs 17(3):155–167

    Article  CAS  PubMed  Google Scholar 

  38. Terando AM, Faries MB, Morton DL (2007) Vaccine therapy for melanoma: current status and future directions. Vaccine 25(Suppl 2):B4–B16

    Article  CAS  PubMed  Google Scholar 

  39. Durrant LG, Noble P, Spendlove I (2012) Immunology in the clinic review series; focus on cancer: glycolipids as targets for tumour immunotherapy. Clin Exp Immunol 167(2):206–215

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Chu KU, Ravindranath MH, Gonzales A, Nishimoto K, Tam WY, Soh D et al (2000) Gangliosides as targets for immunotherapy for pancreatic adenocarcinoma. Cancer 88(8):1828–1836

    Article  CAS  PubMed  Google Scholar 

  41. Sommers SC, Meissner WA (1954) Unusual carcinomas of the pancreas. AMA Arch Pathol 58(2):101–111

    CAS  PubMed  Google Scholar 

  42. Brat DJ, Lillemoe KD, Yeo CJ, Warfield PB, Hruban RH (1998) Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol 22(2):163–169

    Article  CAS  PubMed  Google Scholar 

  43. Brockie E, Anand A, Albores-Saavedra J (1998) Progression of atypical ductal hyperplasia/carcinoma in situ of the pancreas to invasive adenocarcinoma. Ann Diagn Pathol 2(5):286–292

    Article  CAS  PubMed  Google Scholar 

  44. Hruban RH, Goggins M, Parsons J, Kern SE (2000) Progression model for pancreatic cancer. Clin Cancer Res 6(8):2969–2972

    CAS  PubMed  Google Scholar 

  45. Day JD, Digiuseppe JA, Yeo C, Lai-Goldman M, Anderson SM, Goodman SN et al (1996) Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum Pathol 27(2):119–124

    Article  CAS  PubMed  Google Scholar 

  46. Hannun YA, Obeid LM (2011) Many ceramides. J Biol Chem 286(32):27855–27862

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Pinto SN, Silva LC, Futerman AH, Prieto M (2011) Effect of ceramide structure on membrane biophysical properties: the role of acyl chain length and unsaturation. Biochim Biophys Acta 1808(11):2753–2760

    Article  CAS  PubMed  Google Scholar 

  48. Gottesman MM, Ling V (2006) The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett 580(4):998–1009

    Article  CAS  PubMed  Google Scholar 

  49. Liu YY, Han TY, Giuliano AE, Cabot MC (2001) Ceramide glycosylation potentiates cellular multidrug resistance. FASEB J 15(3):719–730

    Article  CAS  PubMed  Google Scholar 

  50. Radin NS (1999) Chemotherapy by slowing glucosphingolipid synthesis. Biochem Pharmacol 57(6):589–595

    Article  CAS  PubMed  Google Scholar 

  51. Messner MC, Cabot MC (2010) Glucosylceramide in humans. Adv Exp Med Biol 688:156–164

    Article  CAS  PubMed  Google Scholar 

  52. Gouaze-Andersson V, Cabot MC (2006) Glycosphingolipids and drug resistance. Biochim Biophys Acta 1758(12):2096–2103

    Article  CAS  PubMed  Google Scholar 

  53. Morad SA, Madigan JP, Levin JC, Abdelmageed N, Karimi R, Rosenberg DW et al (2013) Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53. Biochem Pharmacol 85(8):1057–1065

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Lucci A, Cho WI, Han TY, Giuliano AE, Morton DL, Cabot MC (1998) Glucosylceramide: a marker for multiple-drug resistant cancers. Anticancer Res 18(1B):475–480

    CAS  PubMed  Google Scholar 

  58. Musumarra G, Barresi V, Condorelli DF, Scire S (2003) A bioinformatic approach to the identification of candidate genes for the development of new cancer diagnostics. Biol Chem 384(2):321–327

    Article  CAS  PubMed  Google Scholar 

  59. Zeidan YH, Jenkins RW, Korman JB, Liu X, Obeid LM, Norris JS et al (2008) Molecular targeting of acid ceramidase: implications to cancer therapy. Curr Drug Targets 9(8):653–661

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Orr Gandy KA, Obeid LM (2013) Targeting the sphingosine kinase/sphingosine 1-phosphate pathway in disease: review of sphingosine kinase inhibitors. Biochim Biophys Acta 1831(1):157–166

    Article  CAS  PubMed  Google Scholar 

  61. Ogretmen B, Pettus BJ, Rossi MJ, Wood R, Usta J, Szulc Z et al (2002) Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide. J Biol Chem 277(15):12960–12969

    Article  CAS  PubMed  Google Scholar 

  62. Jiang Y, DiVittore NA, Young MM, Jia Z, Xie K, Ritty TM et al (2013) Altered sphingolipid metabolism in patients with metastatic pancreatic cancer. Biomolecules 3(3):435–448

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  63. Dimanche-Boitrel MT, Rebillard A (2013) Sphingolipids and response to chemotherapy. Handb Exp Pharmacol 216:73–91

    Article  CAS  PubMed  Google Scholar 

  64. Wang H, Maurer BJ, Reynolds CP, Cabot MC (2001) N-(4-hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase. Cancer Res 61(13):5102–5105

    CAS  PubMed  Google Scholar 

  65. Messner MC, Cabot MC (2011) Cytotoxic responses to N-(4-hydroxyphenyl)retinamide in human pancreatic cancer cells. Cancer Chemother Pharmacol 68(2):477–487

    Article  CAS  PubMed  Google Scholar 

  66. Maurer BJ, Kang MH, Villablanca JG, Janeba J, Groshen S, Matthay KK et al (2013) Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium. Pediatr Blood Cancer 60(11):1801–1808

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  68. Zhang S, Zhou J, Zhang C, Wu H, Wang Y, Bian J et al (2012) Arsenic trioxide inhibits HCCLM3 cells invasion through de novo ceramide synthesis and sphingomyelinase-induced ceramide production. Med Oncol 29(3):2251–2260

    Article  CAS  PubMed  Google Scholar 

  69. Rath G, Schneider C, Langlois B, Sartelet H, Morjani H, Btaouri HE et al (2009) De novo ceramide synthesis is responsible for the anti-tumor properties of camptothecin and doxorubicin in follicular thyroid carcinoma. Int J Biochem Cell Biol 41(5):1165–1172

    Article  CAS  PubMed  Google Scholar 

  70. Charles AG, Han TY, Liu YY, Hansen N, Giuliano AE, Cabot MC (2001) Taxol-induced ceramide generation and apoptosis in human breast cancer cells. Cancer Chemother Pharmacol 47(5):444–450

    Article  CAS  PubMed  Google Scholar 

  71. Wang H, Giuliano AE, Cabot MC (2002) Enhanced de novo ceramide generation through activation of serine palmitoyltransferase by the P-glycoprotein antagonist SDZ PSC 833 in breast cancer cells. Mol Cancer Ther 1(9):719–726

    CAS  PubMed  Google Scholar 

  72. Senchenkov A, Han TY, Wang H, Frankel AE, Kottke TJ, Kaufmann SH et al (2001) Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT(388)-granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF. Blood 98(6):1927–1934

    Article  CAS  PubMed  Google Scholar 

  73. Melnik MK, Webb CP, Richardson PJ, Luttenton CR, Campbell AD, Monroe TJ et al (2010) Phase II trial to evaluate gemcitabine and etoposide for locally advanced or metastatic pancreatic cancer. Mol Cancer Ther 9(8):2423–2429

    Article  CAS  PubMed  Google Scholar 

  74. Zhang SH, Huang Q (2013) Etoposide induces apoptosis via the mitochondrial- and caspase-dependent pathways and in non-cancer stem cells in Panc-1 pancreatic cancer cells. Oncol Rep 30(6):2765–2770

    CAS  PubMed  Google Scholar 

  75. Cabot MC, Han TY, Giuliano AE (1998) The multidrug resistance modulator SDZ PSC 833 is a potent activator of cellular ceramide formation. FEBS Lett 431(2):185–188

    Article  CAS  PubMed  Google Scholar 

  76. Cabot MC, Giuliano AE, Han TY, Liu YY (1999) SDZ PSC 833, the cyclosporine A analogue and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitive and drug-resistant cancer cells. Cancer Res 59(4):880–885

    CAS  PubMed  Google Scholar 

  77. Morad SA, Messner MC, Levin JC, Abdelmageed N, Park H, Merrill AH Jr et al (2013) Potential role of acid ceramidase in conversion of cytostatic to cytotoxic end-point in pancreatic cancer cells. Cancer Chemother Pharmacol 71(3):635–645

    Article  CAS  PubMed  Google Scholar 

  78. Liu X, Cheng JC, Turner LS, Elojeimy S, Beckham TH, Bielawska A et al (2009) Acid ceramidase upregulation in prostate cancer: role in tumor development and implications for therapy. Expert Opin Ther Targets 13(12):1449–1458

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Camacho L, Meca-Cortes O, Abad JL, Garcia S, Rubio N, Diaz A et al (2013) Acid ceramidase as a therapeutic target in metastatic prostate cancer. J Lipid Res 54(5):1207–1220

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Maurer BJ, Melton L, Billups C, Cabot MC, Reynolds CP (2000) Synergistic cytotoxicity in solid tumor cell lines between N-(4-hydroxyphenyl)retinamide and modulators of ceramide metabolism. J Natl Cancer Inst 92(23):1897–1909

    Article  CAS  PubMed  Google Scholar 

  81. Hail N Jr, Kim HJ, Lotan R (2006) Mechanisms of fenretinide-induced apoptosis. Apoptosis 11(10):1677–1694

    Article  CAS  PubMed  Google Scholar 

  82. Walsh D, Nelson KA, Mahmoud FA (2003) Established and potential therapeutic applications of cannabinoids in oncology. Support Care Cancer 11(3):137–143

    PubMed  Google Scholar 

  83. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR et al (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB(1) and CB(2). Pharmacol Rev 62(4):588–631

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Brandi J, Dando I, Palmieri M, Donadelli M, Cecconi D (2013) Comparative proteomic and phosphoproteomic profiling of pancreatic adenocarcinoma cells treated with CB1 or CB2 agonists. Electrophoresis 34(9-10):1359–1368

    Article  CAS  PubMed  Google Scholar 

  85. Dando I, Donadelli M, Costanzo C, Dalla Pozza E, D'Alessandro A, Zolla L et al (2013) Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis 4, e664

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Carracedo A, Gironella M, Lorente M, Garcia S, Guzman M, Velasco G et al (2006) Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 66(13):6748–6755

    Article  CAS  PubMed  Google Scholar 

  87. Vasseur S, Vidal Mallo G, Fiedler F, Bodeker H, Canepa E, Moreno S et al (1999) Cloning and expression of the human p8, a nuclear protein with mitogenic activity. Eur J Biochem 259(3):670–675

    Article  CAS  PubMed  Google Scholar 

  88. Malicet C, Lesavre N, Vasseur S, Iovanna JL (2003) p8 inhibits the growth of human pancreatic cancer cells and its expression is induced through pathways involved in growth inhibition and repressed by factors promoting cell growth. Mol Cancer 2:37

    Article  PubMed Central  PubMed  Google Scholar 

  89. Sanchez C, de Ceballos ML, Gomez del Pulgar T, Rueda D, Corbacho C, Velasco G et al (2001) Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 61(15):5784–9

    CAS  PubMed  Google Scholar 

  90. Salazar M, Carracedo A, Salanueva IJ, Hernandez-Tiedra S, Lorente M, Egia A et al (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 119(5):1359–1372

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Xing SS, Shen CC, Godard MP, Wang JJ, Yue YY, Yang ST et al (2014) Bortezomib inhibits C2C12 growth by inducing cell cycle arrest and apoptosis. Biochem Biophys Res Commun 445(2):375–380

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Kretowski R, Borzym-Kluczyk M, Cechowska-Pasko M (2014) Efficient induction of apoptosis by proteasome inhibitor: bortezomib in the human breast cancer cell line MDA-MB-231. Mol Cell Biochem 389(1–2):177–185

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Hou DR, Huang AC, Shiau CW, Wang CY, Yu HC, Chen KF (2013) Bortezomib congeners induce apoptosis of hepatocellular carcinoma via CIP2A inhibition. Molecules 18(12):15398–15411

    Article  CAS  PubMed  Google Scholar 

  94. Gong L, Yang B, Xu M, Cheng B, Tang X, Zheng P et al (2014) Bortezomib-induced apoptosis in cultured pancreatic cancer cells is associated with ceramide production. Cancer Chemother Pharmacol 73(1):69–77

    Article  CAS  PubMed  Google Scholar 

  95. Wang H, Cao Q, Dudek AZ (2012) Phase II study of panobinostat and bortezomib in patients with pancreatic cancer progressing on gemcitabine-based therapy. Anticancer Res 32(3):1027–1031

    CAS  PubMed  Google Scholar 

  96. Nawrocki ST, Carew JS, Dunner K Jr, Boise LH, Chiao PJ, Huang P et al (2005) Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res 65(24):11510–11519

    Article  CAS  PubMed  Google Scholar 

  97. Lauricella M, Emanuele S, D'Anneo A, Calvaruso G, Vassallo B, Carlisi D et al (2006) JNK and AP-1 mediate apoptosis induced by bortezomib in HepG2 cells via FasL/caspase-8 and mitochondria-dependent pathways. Apoptosis 11(4):607–625

    Article  CAS  PubMed  Google Scholar 

  98. Yu C, Rahmani M, Dent P, Grant S (2004) The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. Exp Cell Res 295(2):555–566

    Article  CAS  PubMed  Google Scholar 

  99. Beckham TH, Lu P, Jones EE, Marrison T, Lewis CS, Cheng JC et al (2013) LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria. J Pharmacol Exp Ther 344(1):167–178

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  101. Modrak DE, Leon E, Goldenberg DM, Gold DV (2009) Ceramide regulates gemcitabine-induced senescence and apoptosis in human pancreatic cancer cell lines. Mol Cancer Res 7(6):890–896

    Article  CAS  PubMed  Google Scholar 

  102. Chapman JV, Gouaze-Andersson V, Messner MC, Flowers M, Karimi R, Kester M et al (2010) Metabolism of short-chain ceramide by human cancer cells–implications for therapeutic approaches. Biochem Pharmacol 80(3):308–315

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Gopal P, Rehman RU, Chadha KS, Qiu M, Colella R (2006) Matrigel influences morphology and cathepsin B distribution of prostate cancer PC3 cells. Oncol Rep 16(2):313–320

    CAS  PubMed  Google Scholar 

  104. Zhu QY, Wang Z, Ji C, Cheng L, Yang YL, Ren J et al (2011) C6-ceramide synergistically potentiates the anti-tumor effects of histone deacetylase inhibitors via AKT dephosphorylation and alpha-tubulin hyperacetylation both in vitro and in vivo. Cell Death Dis 2, e117

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  105. Wu CH, Cao C, Kim JH, Hsu CH, Wanebo HJ, Bowen WD et al (2012) Trojan-horse nanotube on-command intracellular drug delivery. Nano Lett 12(11):5475–5480

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Cecco S, Aliberti M, Baldo P, Giacomin E, Leone R (2014) Safety and efficacy evaluation of albumin-bound paclitaxel. Expert Opin Drug Saf 13(4):511–520

    Article  CAS  PubMed  Google Scholar 

  107. Qiu L, Zhou C, Sun Y, Di W, Scheffler E, Healey S et al (2006) Paclitaxel and ceramide synergistically induce cell death with transient activation of EGFR and ERK pathway in pancreatic cancer cells. Oncol Rep 16(4):907–913

    CAS  PubMed  Google Scholar 

  108. Shida D, Takabe K, Kapitonov D, Milstien S, Spiegel S (2008) Targeting SphK1 as a new strategy against cancer. Curr Drug Targets 9(8):662–673

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Pan S, Brentnall TA, Kelly K, Chen R (2013) Tissue proteomics in pancreatic cancer study: discovery, emerging technologies, and challenges. Proteomics 13(3–4):710–721

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Bose R, Verheij M, Haimovitz-Friedman A, Scotto K, Fuks Z, Kolesnick R (1995) Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82(3):405–414

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  112. Ito D, Fujimoto K, Mori T, Kami K, Koizumi M, Toyoda E et al (2006) In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer. Int J Cancer 118(9):2337–2343

    Article  CAS  PubMed  Google Scholar 

  113. Takeda A, Osaki M, Adachi K, Honjo S, Ito H (2004) Role of the phosphatidylinositol 3′-kinase-Akt signal pathway in the proliferation of human pancreatic ductal carcinoma cell lines. Pancreas 28(3):353–358

    Article  CAS  PubMed  Google Scholar 

  114. Bondar VM, Sweeney-Gotsch B, Andreeff M, Mills GB, McConkey DJ (2002) Inhibition of the phosphatidylinositol 3′-kinase-AKT pathway induces apoptosis in pancreatic carcinoma cells in vitro and in vivo. Mol Cancer Ther 1(12):989–997

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, 115 Heart Drive, Greenville, NC, 27835, USA

    Samy A. F. Morad & Myles C. Cabot

  2. Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt

    Samy A. F. Morad

Authors
  1. Samy A. F. Morad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myles C. Cabot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Myles C. Cabot .

Editor information

Editors and Affiliations

  1. Stony Brook University, Stony Brook Cancer Center, Stony Brook, New York, USA

    Yusuf A. Hannun

  2. Dept. of Physiology & Biophysics, Stony Brook University, Stony Brook, New York, USA

    Chiara Luberto

  3. Dept. of Medicine, Stony Brook University, Stony Brook, New York, USA

    Cungui Mao

  4. Dept. of Medicine, Stony Brook University, Stony Brook, New York, USA

    Lina Marie Obeid

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Morad, S.A.F., Cabot, M.C. (2015). Pancreatic Cancer and Sphingolipids. In: Hannun, Y., Luberto, C., Mao, C., Obeid, L. (eds) Bioactive Sphingolipids in Cancer Biology and Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-20750-6_10

Download citation

Publish with us

Policies and ethics

Search

Navigation