Sphingosine 1-phosphate (S1P) is a bioactive lipid metabolite associated with cancer cell proliferation, survival, migration and regulation of tumor angiogenesis in various cellular and animal models. Sphingosine kinase-1 (SphK1) and S1P lyase are the main enzymes that respectively control the synthesis and degradation of S1P. The present study analyzed the prognostic and predictive value of SphK1 and S1P lyase expression in patients with non-small cell lung cancer (NSCLC), treated with either surgery alone or in combination with adjuvant carboplatin and navelbine. Formalin-fixed, paraffin-embedded tissue samples from 176 patients with NSCLC were stained immunohistochemically using antibodies against SphK1 and S1P lyase, and their expression was correlated with all available clinicopathological factors. Increased expression of SphK1 was significantly associated with shorter overall and disease free survival in patients treated with adjuvant platinum-based chemotherapy. No prognostic relevance for S1P lyase expression was observed. Collectively, the results suggest that the immunohistochemical detection of SphK1 may be a promising predictive marker in NSCLC patients treated with adjuvant platinum-based chemotherapy.

1st Department of Surgery Faculty of Medicine and Dentistry Palacký University and Faculty Hospital in Olomouc 77900 Olomouc Czech Republic

Centre for Cancer Biology University of South Australia and SA Pathology Adelaide SA5000 Australia

Department of Clinical and Molecular Pathology Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University 77515 Olomouc Czech Republic

Department of Tuberculosis and Respiratory Diseases Faculty of Medicine and Dentistry Palacký University and Faculty Hospital in Olomouc 77900 Olomouc Czech Republic

Equipe Labellisée Ligue contre le Cancer 75013 Paris France

Faculty of Medicine and Dentistry Palacký University Olomouc 77515 Olomouc Czech Republic

Institut de Pharmacologie et de Biologie Structurale Université de Toulouse CNRS UPS 31077 Toulouse France

See more in PubMed

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107. PubMed DOI

Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J, International Adjuvant Lung Cancer Trial Collaborative Group Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351–360. doi: 10.1056/NEJMoa031644. PubMed DOI

Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, Dunant A, Torri V, Rosell R, Seymour L, et al. LACE Collaborative Group Lung adjuvant cisplatin evaluation: A pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552–3559. doi: 10.1200/JCO.2007.13.9030. PubMed DOI

Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, Le Groumellec A, Lorusso V, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial. Lancet Oncol. 2006;7:719–727. doi: 10.1016/S1470-2045(06)70804-X. PubMed DOI

Zatloukal P, Petruzelka L, Zemanova M, Havel L, Janku F, Judas L, Kubik A, Krepela E, Fiala P, Pecen L. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: A randomized study. Lung Cancer. 2004;46:87–98. doi: 10.1016/j.lungcan.2004.03.004. PubMed DOI

Scheper RJ, Broxterman HJ, Scheffer GL, Kaaijk P, Dalton WS, van Heijningen TH, van Kalken CK, Slovak ML, de Vries EG, van der Valk P, et al. Overexpression of a M(r) 110,000 vesicular protein in non-P-glycoprotein-mediated multidrug resistance. Cancer Res. 1993;53:1475–1479. PubMed

Marchetti S, de Vries NA, Buckle T, Bolijn MJ, van Eijndhoven MA, Beijnen JH, Mazzanti R, van Tellingen O, Schellens JH. Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice. Mol Cancer Ther. 2008;7:2280–2287. doi: 10.1158/1535-7163.MCT-07-2250. PubMed DOI

Ozvegy-Laczka C, Cserepes J, Elkind NB, Sarkadi B. Tyrosine kinase inhibitor resistance in cancer: Role of ABC multidrug transporters. Drug Resist Updat. 2005;8:15–26. doi: 10.1016/j.drup.2005.02.002. PubMed DOI

Berger W, Setinek U, Hollaus P, Zidek T, Steiner E, Elbling L, Cantonati H, Attems J, Gsur A, Micksche M. Multidrug resistance markers P-glycoprotein, multidrug resistance protein 1, and lung resistance protein in non-small cell lung cancer: Prognostic implications. J Cancer Res Clin Oncol. 2005;131:355–363. doi: 10.1007/s00432-004-0653-9. PubMed DOI

Ikuta K, Takemura K, Sasaki K, Kihara M, Nishimura M, Ueda N, Naito S, Lee E, Shimizu E, Yamauchi A. Expression of multidrug resistance proteins and accumulation of cisplatin in human non-small cell lung cancer cells. Biol Pharm Bull. 2005;28:707–712. doi: 10.1248/bpb.28.707. PubMed DOI

Berger W, Elbling L, Hauptmann E, Micksche M. Expression of the multidrug resistance-associated protein (MRP) and chemoresistance of human non-small-cell lung cancer cells. Int J Cancer. 1997;73:84–93. doi: 10.1002/(SICI)1097-0215(19970926)73:1<84::AID-IJC14>3.0.CO;2-5. PubMed DOI

Yano K. Lipid metabolic pathways as lung cancer therapeutic targets: A computational study. Int J Mol Med. 2012;29:519–529. doi: 10.3892/ijmm.2011.876. PubMed DOI PMC

Futerman AH, Hannun YA. The complex life of simple sphingolipids. EMBO Rep. 2004;5:777–782. doi: 10.1038/sj.embor.7400208. PubMed DOI PMC

Cuvillier O, Levade T. Enzymes of sphingosine metabolism as potential pharmacological targets for therapeutic intervention in cancer. Pharmacol Res. 2003;47:439–445. doi: 10.1016/S1043-6618(03)00053-7. PubMed DOI

Morad SA, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer. 2013;13:51–65. doi: 10.1038/nrc3398. PubMed DOI

Cuvillier O. Sphingosine in apoptosis signaling. Biochim Biophys Acta. 2002;1585:153–162. doi: 10.1016/S1388-1981(02)00336-0. PubMed DOI

Pitson SM. Regulation of sphingosine kinase and sphingolipid signaling. Trends Biochem Sci. 2011;36:97–107. doi: 10.1016/j.tibs.2010.08.001. PubMed DOI

Maceyka M, Harikumar KB, Milstien S, Spiegel S. Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol. 2012;22:50–60. doi: 10.1016/j.tcb.2011.09.003. PubMed DOI PMC

Cuvillier O, Ader I, Bouquerel P, Brizuela L, Gstalder C, Malavaud B. Hypoxia, therapeutic resistance, and sphingosine 1-phosphate. Adv Cancer Res. 2013;117:117–141. doi: 10.1016/B978-0-12-394274-6.00005-4. PubMed DOI

Mendelson K, Evans T, Hla T. Sphingosine 1-phosphate signalling. Development. 2014;141:5–9. doi: 10.1242/dev.094805. PubMed DOI PMC

Cuvillier O. Downregulating sphingosine kinase-1 for cancer therapy. Expert Opin Ther Targets. 2008;12:1009–1020. doi: 10.1517/14728222.12.8.1009. PubMed DOI

Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind S, Spiegel S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 1996;381:800–803. doi: 10.1038/381800a0. PubMed DOI

Bonhoure E, Pchejetski D, Aouali N, Morjani H, Levade T, Kohama T, Cuvillier O. Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1. Leukemia. 2006;20:95–102. doi: 10.1038/sj.leu.2404023. PubMed DOI

Pchejetski D, Golzio M, Bonhoure E, Calvet C, Doumerc N, Garcia V, Mazerolles C, Rischmann P, Teissié J, Malavaud B, et al. Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res. 2005;65:11667–11675. doi: 10.1158/0008-5472.CAN-05-2702. PubMed DOI

Guillermet-Guibert J, Davenne L, Pchejetski D, Saint-Laurent N, Brizuela L, Guilbeau-Frugier C, Delisle MB, Cuvillier O, Susini C, Bousquet C. Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug. Mol Cancer Ther. 2009;8:809–820. doi: 10.1158/1535-7163.MCT-08-1096. PubMed DOI

Pchejetski D, Bohler T, Brizuela L, Sauer L, Doumerc N, Golzio M, Salunkhe V, Teissié J, Malavaud B, Waxman J, et al. FTY720 (fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1. Cancer Res. 2010;70:8651–8661. doi: 10.1158/0008-5472.CAN-10-1388. PubMed DOI

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;11:1841–1851. doi: 10.1158/1535-7163.MCT-12-0227. PubMed DOI

Gstalder C, Ader I, Cuvillier O. FTY720 (Fingolimod) Inhibits HIF1 and HIF2 Signaling, Promotes Vascular Remodeling, and Chemosensitizes in Renal Cell Carcinoma Animal Model. Mol Cancer Ther. 2016;15:2465–2474. doi: 10.1158/1535-7163.MCT-16-0167. PubMed DOI

Ito H, Yoshida K, Murakami M, Hagiwara K, Sasaki N, Kobayashi M, Takagi A, Kojima T, Sobue S, Suzuki M. Heterogeneous sphingosine-1-phosphate lyase gene expression and its regulatory mechanism in human lung cancer cell lines. Biochim Biophys Acta. 2011;1811:119–128. doi: 10.1016/j.bbalip.2010.12.005. PubMed DOI

Song L, Xiong H, Li J, Liao W, Wang L, Wu J, Li M. Sphingosine kinase-1 enhances resistance to apoptosis through activation of PI3K/Akt/NF-κB pathway in human non-small cell lung cancer. Clin Cancer Res. 2011;17:1839–1849. doi: 10.1158/1078-0432.CCR-10-0720. PubMed DOI

Li J, Guan HY, Gong LY, Song LB, Zhang N, Wu J, Yuan J, Zheng YJ, Huang ZS, Li M. Clinical significance of sphingosine kinase-1 expression in human astrocytomas progression and overall patient survival. Clin Cancer Res. 2008;14:6996–7003. doi: 10.1158/1078-0432.CCR-08-0754. PubMed DOI

Zhang Y, Wang Y, Wan Z, Liu S, Cao Y, Zeng Z. Sphingosine kinase 1 and cancer: A systematic review and meta-analysis. PLoS One. 2014;9:e90362. doi: 10.1371/journal.pone.0090362. PubMed DOI PMC

Ruckhäberle E, Karn T, Denkert C, Loibl S, Ataseven B, Reimer T, Becker S, Holtrich U, Rody A, Darb-Esfahani S, et al. Predictive value of sphingosine kinase 1 expression in neoadjuvant treatment of breast cancer. J Cancer Res Clin Oncol. 2013;139:1681–1689. doi: 10.1007/s00432-013-1490-5. PubMed DOI PMC

Sutphen R, Xu Y, Wilbanks GD, Fiorica J, Grendys EC, Jr, LaPolla JP, Arango H, Hoffman MS, Martino M, Wakeley K, et al. Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2004;13:1185–1191. PubMed

Malavaud B, Pchejetski D, Mazerolles C, de Paiva GR, Calvet C, Doumerc N, Pitson S, Rischmann P, Cuvillier O. Sphingosine kinase-1 activity and expression in human prostate cancer resection specimens. Eur J Cancer. 2010;46:3417–3424. doi: 10.1016/j.ejca.2010.07.053. PubMed DOI

Serra M, Saba JD. Sphingosine 1-phosphate lyase, a key regulator of sphingosine 1-phosphate signaling and function. Adv Enzyme Regul. 2010;50:349–362. doi: 10.1016/j.advenzreg.2009.10.024. PubMed DOI PMC

Oskouian B, Sooriyakumaran P, Borowsky AD, Crans A, Dillard-Telm L, Tam YY, Bandhuvula P, Saba JD. Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. Proc Natl Acad Sci USA. 2006;103:17384–17389. doi: 10.1073/pnas.0600050103. PubMed DOI PMC

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;3:287–296. doi: 10.1158/1541-7786.MCR-04-0197. PubMed DOI

Johnson KR, Johnson KY, Crellin HG, Ogretmen B, Boylan AM, Harley RA, Obeid LM. Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem. 2005;53:1159–1166. doi: 10.1369/jhc.4A6606.2005. PubMed DOI

Qin L, Liu S, Qin M, Wu W, Qin N, Fu Z, Xu C, Huang J, Lai M. Down-regulation of sphingosine kinase 1 (SphK1) enhances the chemosensitivity to cisplatin in human colon cancer RKO cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017;33:623–629. (In Chinese) PubMed

Matula K, Collie-Duguid E, Murray G, Parikh K, Grabsch H, Tan P, Lalwani S, Garau R, Ong Y, Bain G, et al. Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer. BMC Cancer. 2015;15:762. doi: 10.1186/s12885-015-1718-7. PubMed DOI PMC

Gao J, Tian ML, Song LP. The role of SPHK-1 in non-small cell lung cancer drug-resistant cell line H460. J Xi'an Jiaotong Univ. 2017;38:172–175. (In Chinese)