Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

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.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

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

References

  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.

    PubMed  CAS  Google Scholar 

  2. Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer. 2004;4:604–16.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  6. Milstien S, Spiegel S. Targeting sphingosine-1-phosphate: a novel avenue for cancer therapeutics. Cancer Cell. 2006;9:148–50.

    Article  PubMed  CAS  Google Scholar 

  7. French KJ, Schrecengost RS, Lee BD, et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 2003;63:5962–9.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  9. Kawamori T, Osta W, Johnson KR, et al. Sphingosine kinase 1 is up-regulated in colon carcinogenesis. FASEB J. 2006;20:386–8.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  23. Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–7.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  28. Pallis M. Sphingosine kinase inhibitors in the apoptosis of leukaemia cells. Leuk Res. 2002;26:415–6.

    Article  PubMed  Google Scholar 

  29. Ricci C, Onida F, Ghidoni R. Sphingolipid players in the leukemia arena. Biochim Biophys Acta. 2006;1758:2121–32.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Medical Technology, Nagoya University Graduate School of Health Sciences, Daiko minami 1-1-20, Higashi-ku, Nagoya, 461-8673, Japan

    S. Sobue, M. Murakami, H. Ito, A. Kimura, S. Gao, A. Furuhata, A. Takagi, T. Kojima & T. Murate

  2. Department of Biochemistry, Gifu Pharmaceutical University, Gifu, Japan

    S. Nemoto

  3. Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan

    M. Nakamura

  4. Department of Pharmacy, Gifu University Graduate School of Medicine, Gifu, Japan

    Y. Ito

  5. Department of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine, Nagoya, Japan

    M. Suzuki

  6. Department of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, Japan

    Y. Banno

  7. Gifu International Institute of Biotechnology, Kakamigahara, Japan

    Y. Nozawa

Authors
  1. S. Sobue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Nemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Furuhata
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T. Kojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M. Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Y. Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M. Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Y. Banno
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Y. Nozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. T. Murate
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. Murate.

About this article

Cite this article

Sobue, S., Nemoto, S., Murakami, M. et al. Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells. Int J Hematol 87, 266–275 (2008). https://doi.org/10.1007/s12185-008-0052-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-008-0052-0

Keywords

Search

Navigation