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International Journal of Hematology

, Volume 87, Issue 3, pp 266–275 | Cite as

Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells

  • S. Sobue
  • S. Nemoto
  • M. Murakami
  • H. Ito
  • A. Kimura
  • S. Gao
  • A. Furuhata
  • A. Takagi
  • T. Kojima
  • M. Nakamura
  • Y. Ito
  • M. Suzuki
  • Y. Banno
  • Y. Nozawa
  • T. Murate
Original Article

Abstract

We recently reported increased sphingosine kinase 1 (SPHK1) and decreased neutral sphingomyelinase 2 (NSMase2) gene expression in myelodysplastic syndromes and acute leukemia. This alteration is supposed to change the cellular sphingolipid metabolites; however, positive correlations were observed between daunorubicin (DA)-IC50 and the SPHK1 message but not between DA-IC50 and NSMase2 messages, when 16 different leukemia cell lines were used to analyze the relationship between gene expressions and chemosensitivity against DA. Using two cell lines with either the highest or lowest SPHK1 expression, cellular ceramides and sphingosine 1-phosphate (S1P) were quantified by liquid chromatography/mass spectrometry. Increased ceramide was observed in DA-sensitive, but not in DA-resistant cell lines treated with low doses of DA. Upon DA treatment, S1P decreased more in the sensitive cell lines than in resistant cell lines. A SPHK inhibitor recovered the DA sensitivity of DA-resistant cells. The modulation of SPHK1 gene expression by either overexpression or using siRNA affected the DA sensitivity of representative cell lines. Results clearly show that SPHK1 is both a good marker to predict the DA sensitivity of leukemia cells and a potential therapeutic target for leukemia with high SPHK1 expression, and suggest that the sphingolipid rheostat plays a significant role in DA-induced cytotoxicity.

Keywords

Sphingosine kinase 1 Daunorubicin Chemosensitivity Ceramide Sphingosine 1-phosphate 

Abbreviations

DA

Daunorubicin

SPHK

Sphingosine kinase

NSMase

Neutral sphingomyelinase

S1P

Sphingosine 1-phosphate

C16 ceramide

N-Hexadecanoyl-d-erythro-sphingosine

DMS

Dimethyl sphingosine

C18 ceramide

N-Octadecanoyl-d-erythro-sphingosine

C24 ceramide

N-Tetracosanoyl-d-erythro-sphingosine

RT-PCR

Reverse transcription-polymerase chain reaction

TFA

Trifluoroacetic acid

LC–MS/MS

Liquid chromatography-tandem mass spectrometry

ESI

Electrospray atmospheric pressure ionization

MRM

Multiple reaction monitoring

MDS

Myelodysplastic syndromes

Notes

Acknowledgments

The authors express their sincere thanks to Dr. H. Nagai, Ms. K. Hagiwara (Research Center for Blood Diseases, National Hospital Organization Nagoya Medical Center, Nagoya, Japan), Dr. S.M. Pitson (University of Adelaide, Australia), and Dr. Y.A. Hannun (University of South Carolina, SC, USA) for providing leukemia cell lines and expression vectors. We also express our gratitude to Dr. M. Kyogashima and Dr. K. Koizumi-T. (Aichi Cancer Center, Nagoya, Japan) for their assistance with the ceramide quantification.

References

  1. 1.
    Taha TA, Hannun YA, Obeid LM. Sphingosine kinase: biochemical and cellular regulation and role in disease. J Biochem Mol Biol. 2006;39:113–31.PubMedGoogle Scholar
  2. 2.
    Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer. 2004;4:604–16.PubMedCrossRefGoogle Scholar
  3. 3.
    Olivera A, Kohama T, Edsall L, et al. Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J Cell Biol. 1999;147:545–58.PubMedCrossRefGoogle Scholar
  4. 4.
    Xia P, Wang L, Gamble JR, Vadas MA. Activation of sphingosine kinase by tumor necrosis factor-alpha inhibits apoptosis in human endothelial cells. J Biol Chem. 1999;274:34499–505.PubMedCrossRefGoogle Scholar
  5. 5.
    Pchejetski D, Golzio M, Bonhoure E, et al. Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res. 2005;65:11667–75.PubMedCrossRefGoogle Scholar
  6. 6.
    Milstien S, Spiegel S. Targeting sphingosine-1-phosphate: a novel avenue for cancer therapeutics. Cancer Cell. 2006;9:148–50.PubMedCrossRefGoogle Scholar
  7. 7.
    French KJ, Schrecengost RS, Lee BD, et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 2003;63:5962–9.PubMedGoogle Scholar
  8. 8.
    Johnson KR, Johnson KY, Crellin HG, et al. Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem. 2005;53:1159–66.PubMedCrossRefGoogle Scholar
  9. 9.
    Kawamori T, Osta W, Johnson KR, et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J. 2006;20:386–8.PubMedGoogle Scholar
  10. 10.
    Hayashi Y, Kiyono T, Fujita M, Ishibashi M. cca1 is required for formation of growth-arrested confluent monolayer of rat 3Y1 cells. J Biol Chem. 1997;272:18082–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Marchesini N, Osta W, Bielawski J, Luberto C, Obeid LM, Hannun YA. Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells. J Biol Chem. 2004;279:25101–11.PubMedCrossRefGoogle Scholar
  12. 12.
    Sobue S, Iwasaki T, Sugisaki C, et al. Quantitative RT-PCR analysis of sphingolipid metabolic enzymes in acute leukemia and myelodysplastic syndromes. Leukemia. 2006;20:2042–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Bonhoure E, Pchejetski D, Aouali N, et al. Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1. Leukemia. 2006;20:95–102.PubMedCrossRefGoogle Scholar
  14. 14.
    Akao Y, Banno Y, Nakagawa Y, et al. High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation. Biochem Biophys Res Commun. 2006;342:1284–90.PubMedCrossRefGoogle Scholar
  15. 15.
    Pitson SM, Moretti PA, Zebol JR, et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J. 2003;22:5491–500.PubMedCrossRefGoogle Scholar
  16. 16.
    Pitson SM, Xia P, Leclercq TM, et al. Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J Exp Med. 2005;201:49–54.PubMedCrossRefGoogle Scholar
  17. 17.
    Melendez AJ, Khaw AK. Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells. J Biol Chem. 2002;277:17255–62.PubMedCrossRefGoogle Scholar
  18. 18.
    Nagai H, Li Y, Hatano S, et al. Mutations and aberrant DNA methylation of the PROX1 gene in hematologic malignancies. Genes Chromosomes Cancer. 2003;38:13–21.PubMedCrossRefGoogle Scholar
  19. 19.
    Murakami M, Ichihara M, Sobue S, et al. RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis. J Neurochem. 2007;102:1583–94.CrossRefGoogle Scholar
  20. 20.
    Koda M, Murate T, Wang S, et al. Sphingosine kinase 1 is involved in dibutyryl cyclic AMP-induced granulocytic differentiation through the upregulation of extracellular signal-regulated kinase, but not p38 MAP kinase, in HL60 cells. Biochim Biophys Acta. 2005;1733:101–10.PubMedGoogle Scholar
  21. 21.
    Liu H, Sugiura M, Nava VE, et al. Molecular cloning and functional characterization of a novel mammalian sphigosine kinase type 2 isoform. J Biol Chem. 2000;275:19513–20.PubMedCrossRefGoogle Scholar
  22. 22.
    Sobue S, Hagiwara K, Banno Y, et al. Transcription factor specificity protein 1 (Sp1) is the main regulator of nerve growth factor-induced sphingosine kinase 1 gene expression of the rat pheochromocytoma cell line, PC12. J Neurochem. 2005;95:940–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–7.PubMedGoogle Scholar
  24. 24.
    Baran Y, Salas A, Senkal CE, 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. 2007;282:10922–34.PubMedCrossRefGoogle Scholar
  25. 25.
    Taha TA, Osta W, Kozhaya L, et al. Down-regulation of sphingosine kinase-1 by DNA damage: dependence on proteases and p53. J Biol Chem. 2004;279:20546–54.PubMedCrossRefGoogle Scholar
  26. 26.
    Kanzawa F, Nishio K, Fukuoka K, Fukuda M, Kumimoto T, Saijo N. Evaluation of synergism of a novel three-dimensional model for combined action of cisplatin and etoposide on the growth of a human small-cell lung cancer cell line, SBC-3. Int J Cancer. 1997;71:311–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Li G, Alexander H, Schneider N, Alexander S. Molecular basis for resistance to the anticancer drug cisplatin in Dictyostelium. Microbiology. 2000;146:2219–27.PubMedGoogle Scholar
  28. 28.
    Pallis M. Sphingosine kinase inhibitors in the apoptosis of leukaemia cells. Leuk Res. 2002;26:415–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Ricci C, Onida F, Ghidoni R. Sphingolipid players in the leukemia arena. Biochim Biophys Acta. 2006;1758:2121–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Murate T, Suzuki M, Hattori M, et al. Up-regulation of acid sphingomyelinase during retinoic acid-induced myeloid differentiation of NB4, a human acute promyelocytic leukemia cell line. J Biol Chem. 2002;277:9936–43.PubMedCrossRefGoogle Scholar
  31. 31.
    Venable ME, Webb-Froehlich LM, Sloan EF, Thomley JE. Shift in sphingolipid metabolism leads to an accumulation of ceramide in senescence. Mech Ageing Dev. 2006;127:473–80.PubMedGoogle Scholar
  32. 32.
    Itoh M, Kitano T, Watanabe M, et al. Possible role of ceramide as an indicator of chemoresistance: decrease of the ceramide content via activation of glucosylceramide synthase and sphingomyelin synthase in chemoresistant leukemia. Clin Cancer Res. 2003;9:415–23.PubMedGoogle Scholar
  33. 33.
    Uchida Y, Itoh M, Taguchi Y, et al. Ceramide reduction and transcriptional up-regulation of glucosylceramide synthase through doxorubicin-activated Sp1 in drug-resistant HL-60/ADR cells. Cancer Res. 2004;64:6271–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Eto M, Bennouna J, Hunter OC, Lotze MT, Amoscato AA. Importance of C16 ceramide accumulation during apoptosis in prostate cancer cells. Int J Urol. 2006;13:148–56.PubMedCrossRefGoogle Scholar
  35. 35.
    Zabielski P, Baranowski M, Zendzian-Piotrowska M, Blachnio A, Gorski J. Partial hepatectomy activates production of the pro-mitotic intermediates of the sphingomyelin signal transduction pathway in the rat liver. Prostaglandins Other Lipid Mediat. 2007;83:277–84.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2008

Authors and Affiliations

  • S. Sobue
    • 1
  • S. Nemoto
    • 2
  • M. Murakami
    • 1
  • H. Ito
    • 1
  • A. Kimura
    • 1
  • S. Gao
    • 1
  • A. Furuhata
    • 1
  • A. Takagi
    • 1
  • T. Kojima
    • 1
  • M. Nakamura
    • 3
  • Y. Ito
    • 4
  • M. Suzuki
    • 5
  • Y. Banno
    • 6
  • Y. Nozawa
    • 7
  • T. Murate
    • 1
  1. 1.Department of Medical TechnologyNagoya University Graduate School of Health SciencesNagoyaJapan
  2. 2.Department of BiochemistryGifu Pharmaceutical UniversityGifuJapan
  3. 3.Laboratory of Drug InformaticsGifu Pharmaceutical UniversityGifuJapan
  4. 4.Department of PharmacyGifu University Graduate School of MedicineGifuJapan
  5. 5.Department of Molecular CarcinogenesisNagoya University Graduate School of MedicineNagoyaJapan
  6. 6.Department of Cell SignalingGifu University Graduate School of MedicineGifuJapan
  7. 7.Gifu International Institute of BiotechnologyKakamigaharaJapan

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