Sphingolipids as Determinants of Apoptosis and Chemoresistance in the MCF-7 Cell Model System

Abstract

An estimated 182,640 women and 1,990 men were diagnosed with breast cancer in 2008, and approximately 40,480 women and 450 men died from the disease (1). Thus, continued mechanistic studies are needed to understand the causes and develop additional therapeutics for this complicated disease. The MCF-7 cell system is one of the most recognized models for estrogen receptor (ER)-positive breast cancer and has generated ~13,000 publications cited in PubMed to date. A number of clues for biological mechanisms related to apoptotic/anti-apoptotic pathways and chemoresistance were elucidated and summarized in our previous review (2). The focus of this review is new knowledge of the central role of sphingolipid signaling in apoptotic mechanisms in estrogen receptor-positive breast cancer. The ultimate goal is to target crucial steps in survival signaling pathways that may ultimately provide additional translational solutions to the successful pharmacologic treatment of breast cancer.

Get full access to this article

View all access options for this article.

References

American Cancer Society. Cancer Facts and Figures 2008. Atlanta, GA: American Cancer Society, Inc., 2008.

Simstein R, Burow M, Parker A, Weldon C, Beckman B. Apoptosis, chemoresistance, and breast cancer: insights from the MCF-7 cell model system. Exp Biol Med (Maywood) 228:995–1003, 2003.

Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev 9:139–150, 2008.

Wymann MP, Schneiter R. Lipid signalling in disease. Nat Rev 9:162–176, 2008.

Hannun YA, Obeid LM. The c-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem 277:25847–25850, 2002.

Smith ER, Merrill AH, Obeid LM, Hannun YA. Effects of sphingosine and other sphingolipids on protein kinase C. Methods Enzymol 312:361–373, 2000.

Hla T. Physiological and pathological actions of sphingosine 1-phosphate. Semin Cell Dev Biol 15:513–520, 2004.

Brinkmann V, Lynch KR. FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and auto-immunity. Curr Opin Immunol 14:569–575, 2002.

Budde K, Schmouder RL, Brunkhorst R, Nashan B, Lucker PW, Mayer T, Choudhury S, Skerjanec A, Kraus G, Neumayer HH. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol 13:1073–1083, 2002.

10.

Huwiler A, Pfeilschifter J. New players on the center stage: sphingosine 1-phosphate and its receptors as drug targets. Biochem Pharmacol 75:1893–1900, 2008.

11.

Sabbadini RA. Targeting sphingosine-1-phosphate for cancer therapy. Br J Cancer 95:1131–1135, 2006.

12.

Taha TA, Argraves KM, Obeid LM. Sphingosine-1-phosphate receptors: receptor specificity versus functional redundancy. Biochim Biophys Acta 1682:48–55, 2004.

13.

Alvarez SE, Milstien S, Spiegel S. Autocrine and paracrine roles of sphingosine-1-phosphate. Trends Endocrinol Metab 18:300–307, 2007.

14.

Sukocheva OA, Wang L, Albanese N, Pitson SM, Vadas MA, Xia P. Sphingosine kinase transmits estrogen signaling in human breast cancer cells. Mol Endocrinol 17:2002–2012, 2003.

15.

Nava VE, Hobson JP, Murthy S, Milstien S, Spiegel S. Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. Exp Cell Res 281:115–127, 2002.

16.

Sarkar S, Maceyka M, Hait NC, Paugh SW, Sankala H, Milstien S, Spiegel S. Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells. FEBS Lett 579:5313–5317, 2005.

17.

Ruckhaberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S, Grosch S, Geisslinger G, Holtrich U, Karn T, Kaufmann M. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat 112:41–52, 2008.

18.

Taha TA, El-Alwani M, Hannun YA, Obeid LM. Sphingosine kinase-1 is cleaved by cathepsin B in vitro: identification of the initial cleavage sites for the protease. FEBS Lett 580:6047–6054, 2006.

19.

Brown JM, Wouters BG. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 59:1391–1399, 1999.

20.

Zhivotovsky B, Joseph B, Orrenius S. Tumor radiosensitivity and apoptosis. Exp Cell Res 248:10–17, 1999.

21.

Mesner PW Jr, Budihardjo II, Kaufmann SH. Chemotherapy-induced apoptosis. Adv Pharmacol 41:461–499, 1997.

22.

Salgaller ML, Lodge PA. Use of cellular and cytokine adjuvants in the immunotherapy of cancer. J Surg Oncol 68:122–138, 1998.

23.

Sachs L, Lotem J. Control of programmed cell death in normal and leukemic cells: new implications for therapy. Blood 82:15–21, 1993.

24.

Yang F, Foekens JA, Yu J, Sieuwerts AM, Timmermans M, Klijn JG, Atkins D, Wang Y, Jiang Y. Laser microdissection and microarray analysis of breast tumors reveal ER-alpha related genes and pathways. Oncogene 25:1413–1419, 2006.

25.

Efroni S, Schaefer CF, Buetow KH. Identification of key processes underlying cancer phenotypes using biologic pathway analysis. PLoS One 2:e425, 2007.

26.

Gutierrez LS, Eliza M, Niven-Fairchild T, Naftolin F, Mor G. The Fas/Fas-ligand system: a mechanism for immune evasion in human breast carcinomas. Breast Cancer Res Treat 54:245–253, 1999.

27.

Zhang B, Sun T, Xue L, Han X, Zhang B, Lu N, Shi Y, Tan W, Zhou Y, Zhao D, Zhang X, Guo Y, Lin D. Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer. Carcinogenesis 28:1067–1073, 2007.

28.

Machuca C, Mendoza-Milla C, Cordova E, Mejia S, Covarrubias L, Ventura J, Zentella A. Dexamethasone protection from TNF-alpha-induced cell death in MCF-7 cells requires NF-kappaB and is independent from AKT. BMC Cell Biol 7:9, 2006.

29.

Redondo M, Tellez T, Roldan MJ, Serrano A, Garcia-Aranda M, Gleave ME, Hortas ML, Morell M. Anticlusterin treatment of breast cancer cells increases the sensitivities of chemotherapy and tamoxifen and counteracts the inhibitory action of dexamethasone on chemotherapy-induced cytotoxicity. Breast Cancer Res 9:R86, 2007.

30.

Ausserer WA, Bourrat-Floeck B, Green CJ, Laderoute KR, Sutherland RM. Regulation of c-jun expression during hypoxic and low-glucose stress. Mol Cell Biol 14:5032–5042, 1994.

31.

Weigert A, Tzieply N, von Knethen A, Johann AM, Schmidt H, Geisslinger G, Brune B. Tumor cell apoptosis polarizes macrophages role of sphingosine-1-phosphate. Mol Biol Cell 18:3810–3819, 2007.

32.

Ader I, Brizuela L, Bouquerel P, Malavaud B, Cuvillier O. Sphingosine kinase 1: a new modulator of hypoxia inducible factor 1alpha during hypoxia in human cancer cells. Cancer Res 68:8635–8642, 2008.

33.

Li Q, Engelhardt JF. Interleukin-1beta induction of NFkappaB is partially regulated by H2O2-mediated activation of NFkappaB-inducing kinase. J Biol Chem 281:1495–1505, 2006.

34.

Hait NC, Oskeritzian CA, Paugh SW, Milstien S, Spiegel S. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta 1758:2016–2026, 2006.

35.

Olivier S, Robe P, Bours V. Can NF-kappaB be a target for novel and efficient anti-cancer agents? Biochem Pharmacol 72:1054–1068, 2006.

36.

Weldon CB, Burow ME, Rolfe KW, Clayton JL, Jaffe BM, Beckman BS. NF-kappa B-mediated chemoresistance in breast cancer cells. Surgery 130:143–150, 2001.

37.

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

38.

Montagut C, Tusquets I, Ferrer B, Corominas JM, Bellosillo B, Campas C, Suarez M, Fabregat X, Campo E, Gascon P, Serrano S, Fernandez PL, Rovira A, Albanell J. Activation of nuclear factor-kappa B is linked to resistance to neoadjuvant chemotherapy in breast cancer patients. Endocr Relat Cancer 13:607–616, 2006.

39.

Gu Z, Lee RY, Skaar TC, Bouker KB, Welch JN, Lu J, Liu A, Zhu Y, Davis N, Leonessa F, Brunner N, Wang Y, Clarke R. Association of interferon regulatory factor-1, nucleophosmin, nuclear factor-kappaB, and cyclic AMP response element binding with acquired resistance to Faslodex (ICI 182,780). Cancer Res 62:3428–3437, 2002.

40.

Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, Eppenberger U, Eppenberger-Castori S, Benz CC. Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer 7:59, 2007.

41.

Riggins RB, Zwart A, Nehra R, Clarke R. The nuclear factor kappa B inhibitor parthenolide restores ICI 182,780 (Faslodex; fulvestrant)-induced apoptosis in antiestrogen-resistant breast cancer cells. Mol Cancer Ther 4:33–41, 2005.

42.

Curry EA 3rd, Murry DJ, Yoder C, Fife K, Armstrong V, Nakshatri H, O’Connell M, Sweeney CJ. Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer. Invest New Drugs 22:299–305, 2004.

43.

Takabe K, Paugh SW, Milstien S, Spiegel S. “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev 60:181–195, 2008.

44.

Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 68:826–833, 2008.

45.

Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96:926–935, 2004.

46.

Hart S, Fischer OM, Prenzel N, Zwick-Wallasch E, Schneider M, Hennighausen L, Ullrich A. GPCR-induced migration of breast carcinoma cells depends on both EGFR signal transactivation and EGFR-independent pathways. Biol Chem 386:845–855, 2005.

47.

Sukocheva O, Wadham C, Holmes A, Albanese N, Verrier E, Feng F, Bernal A, Derian CK, Ullrich A, Vadas MA, Xia P. Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1. J Cell Biol 173:301–310, 2006.

48.

Johnston SR, Head J, Pancholi S, Detre S, Martin LA, Smith IE, Dowsett M. Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. Clin Cancer Res 9:524S–532S, 2003.

49.

Wang F, Hansen RK, Radisky D, Yoneda T, Barcellos-Hoff MH, Petersen OW, Turley EA, Bissell MJ. Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts. J Natl Cancer Inst 94:1494–1503, 2002.

50.

Fiebig AA, Zhu W, Hollerbach C, Leber B, Andrews DW. Bcl-XL is qualitatively different from and ten times more effective than Bcl-2 when expressed in a breast cancer cell line. BMC Cancer 6:213, 2006.

51.

Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC. Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci U S A 95:4997–5002, 1998.

52.

Pedram A, Razandi M, Wallace DC, Levin ER. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol Biol Cell 17:2125–2137, 2006.

53.

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

54.

Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, Shelley SA, Nicosia SV, Cheng JQ. Phosphatidylinositol-3-OH kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. Cancer Res 61:5985–5991, 2001.

55.

Ostrakhovitch EA, Cherian MG. Differential regulation of signal transduction pathways in wild type and mutated p53 breast cancer epithelial cells by copper and zinc. Arch Biochem Biophys 423:351–361, 2004.

56.

Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14:381–395, 2002.

57.

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

58.

Zhang M, Fang X, Liu H, Guo R, Wu X, Li B, Zhu F, Ling Y, Griffith BN, Wang S, Yang D. Bioinformatics-based discovery and characterization of an AKT-selective inhibitor 9-chloro-2-methylellipticinium acetate (CMEP) in breast cancer cells. Cancer Lett 252:244–258, 2007.

59.

Sankala HM, Hait NC, Paugh SW, Shida D, Lepine S, Elmore LW, Dent P, Milstien S, Spiegel S. Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin. Cancer Res 67:10466–10474, 2007.

60.

Abukhdeir AM, Vitolo MI, Argani P, De Marzo AM, Karakas B, Konishi H, Gustin JP, Lauring J, Garay JP, Pendleton C, Konishi Y, Blair BG, Brenner K, Garrett-Mayer E, Carraway H, Bachman KE, Park BH. Tamoxifen-stimulated growth of breast cancer due to p21 loss. Proc Natl Acad Sci U S A 105:288–293, 2008.

61.

Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401:86–90, 1999.

62.

Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85, 1999.

63.

Park KJ, Krishnan V, O’Malley BW, Yamamoto Y, Gaynor RB. Formation of an IKKalpha-dependent transcription complex is required for estrogen receptor-mediated gene activation. Mol Cell 18:71–82, 2005.

64.

Silva J, Cavazos DA, Donzis E, Friedrichs WE, Marciniak R, Degraffenried LA. Akt-induced tamoxifen resistance is associated with altered FKHR regulation. Cancer Invest 18 Oct :1–5, 2007 [Epub ahead of print].

65.

Sunters A, Madureira PA, Pomeranz KM, Aubert M, Brosens JJ, Cook SJ, Burgering BM, Coombes RC, Lam EW. Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Cancer Res 66:212–220, 2006.

66.

Boulay A, Rudloff J, Ye J, Zumstein-Mecker S, O’Reilly T, Evans DB, Chen S, Lane HA. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 11:5319–5328, 2005.

67.

Awada A, Cardoso F, Fontaine C, Dirix L, De Greve J, Sotiriou C, Steinseifer J, Wouters C, Tanaka C, Zoellner U, Tang P, Piccart M. The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics. Eur J Cancer 44:84–91, 2008.

68.

Lucci A, Han TY, Liu YY, Giuliano AE, Cabot MC. Multidrug resistance modulators and doxorubicin synergize to elevate ceramide levels and elicit apoptosis in drug-resistant cancer cells. Cancer 86:300–311, 1999.

69.

Cabot MC, Giuliano AE, Han TY, Liu YY. 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 59:880–885, 1999.

70.

Lavieu G, Scarlatti F, Sala G, Carpentier S, Levade T, Ghidoni R, Botti J, Codogno P. Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation. J Biol Chem 281:8518–8527, 2006.

71.

Maurer BJ, Metelitsa LS, Seeger RC, Cabot MC, Reynolds CP. 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.

72.

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

73.

Mehta S, Blackinton D, Omar I, Kouttab N, Myrick D, Klostergaard J, Wanebo H. Combined cytotoxic action of paclitaxel and ceramide against the human Tu138 head and neck squamous carcinoma cell line. Cancer Chemother Pharmacol 46:85–92, 2000.

74.

Struckhoff AP, Bittman R, Burow ME, Clejan S, Elliott S, Hammond T, Tang Y, Beckman BS. Novel ceramide analogs as potential chemotherapeutic agents in breast cancer. J Pharmacol Exp Ther 309:523–532, 2004.

75.

Osuchowski MF, Sharma RP. Fumonisin B1 induces necrotic cell death in BV-2 cells and murine cultured astrocytes and is antiproliferative in BV-2 cells while N2A cells and primary cortical neurons are resistant. Neurotoxicology 26:981–992, 2005.

76.

Smith GW, Constable PD, Foreman JH, Eppley RM, Waggoner AL, Tumbleson ME, Haschek WM. Cardiovascular changes associated with intravenous administration of fumonisin B1 in horses. Am J Vet Res 63:538–545, 2002.

77.

Ito H, Koide N, Hassan F, Islam S, Tumurkhuu G, Mori I, Yoshida T, Kakumu S, Moriwaki H, Yokochi T. Lethal endotoxic shock using alpha-galactosylceramide sensitization as a new experimental model of septic shock. Lab Invest 86:254–261, 2006.

78.

Novgorodov SA, Szulc ZM, Luberto C, Jones JA, Bielawski J, Bielawska A, Hannun YA, Obeid LM. Positively charged ceramide is a potent inducer of mitochondrial permeabilization. J Biol Chem 280:16096–16105, 2005.

79.

Stover TC, Sharma A, Robertson GP, 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.

80.

Bielawska A, Bielawski J, Szulc ZM, Mayroo N, Liu X, Bai A, Elojeimy S, Rembiesa B, Pierce J, Norris JS, Hannun YA. Novel analogs of D-e-MAPP and B13. Part 2: signature effects on bioactive sphingolipids. Bioorg Med Chem 16:1032–1045, 2008.

81.

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

82.

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

83.

Gouaze V, Liu YY, Prickett CS, Yu JY, Giuliano AE, Cabot MC. Glucosylceramide synthase blockade down-regulates P-glycoprotein and resensitizes multidrug-resistant breast cancer cells to anticancer drugs. Cancer Res 65:3861–3867, 2005.

84.

Morgensztern D, McLeod HL. PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs 16:797–803, 2005.

85.

Nagaoka Y, Otsuki K, Fujita T, Uesato S. Effects of phosphorylation of immunomodulatory agent FTY720 (fingolimod) on antiproliferative activity against breast and colon cancer cells. Biol Pharm Bull 31:1177–1181, 2008.

86.

Becker KP, Kitatani K, Idkowiak-Baldys J, Bielawski J, Hannun YA. Selective inhibition of juxtanuclear translocation of protein kinase C betaII by a negative feedback mechanism involving ceramide formed from the salvage pathway. J Biol Chem 280:2606–2612, 2005.

87.

Gouaze-Andersson V, Yu JY, Kreitenberg AJ, Bielawska A, Giuliano AE, Cabot MC. Ceramide and glucosylceramide upregulate expression of the multidrug resistance gene MDR1 in cancer cells. Biochim Biophys Acta 1771:1407–1417, 2007.