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Eukaryotic Cell, June 2004, p. 795-805, Vol. 3, No. 3
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.3.795-805.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Overexpression of Sphingosine-1-Phosphate Lyase or Inhibition of Sphingosine Kinase in Dictyostelium discoideum Results in a Selective Increase in Sensitivity to Platinum-Based Chemotherapy Drugs

Junxia Min, Andrew L. Stegner, Hannah Alexander, and Stephen Alexander*

Division of Biological Sciences, University of Missouri, Columbia, Missouri 65211-7400

Received 26 January 2004/ Accepted 4 March 2004

The efficacy of the chemotherapy drug cisplatin is often limited due to resistance of the tumors to the drug, and increasing the potency of cisplatin without increasing its concentration could prove beneficial. A previously characterized Dictyostelium discoideum mutant with increased resistance to cisplatin was defective in the gene encoding sphingosine-1-phosphate (S-1-P) lyase, which catalyzes the breakdown of S-1-P, an important regulatory molecule in cell function and development and in the regulation of cell fate. We hypothesized that the increased resistance to cisplatin was due to an elevation of S-1-P and predicted that lowering levels of S-1-P should increase sensitivity to the drug. We generated three strains that stably overexpress different levels of the S-1-P lyase. The overexpressor strains have reduced growth rate and, confirming the hypothesis, showed an expression-dependent increase in sensitivity to cisplatin. Consistently, treating the cells with D-erythro-N,N,-dimethylsphingosine, a known inhibitor of sphingosine kinase, increased the sensitivity of mutant and parent cells to cisplatin, while addition of exogenous S-1-P or 8-Br-cyclic AMP made the cells more resistant to cisplatin. The increased sensitivity of the overexpressors to cisplatin was also observed with the cisplatin analog carboplatin. In contrast, the response to doxorubicin, 5-flurouracil, or etoposide was unaffected, indicating that the involvement of the sphingolipid metabolic pathway in modulating the response to cisplatin is not part of a global genotoxic stress response. The augmented sensitivity to cisplatin appears to be the result of an intracellular signaling function of S-1-P, because D. discoideum does not appear to have endothelial differentiation growth (EDG/S1P) receptors. Overall, the results show that modulation of the sphingolipid pathway at multiple points can result in increased sensitivity to cisplatin and has the potential for increasing the clinical usefulness of this important drug.

* Corresponding author. Mailing address: Division of Biological Sciences, 303 Tucker Hall, University of Missouri, Columbia, MO 65211-7400. Phone: (573) 882-6670. Fax: (573) 882-0123. E-mail: alexanderst{at}missouri.edu.

Eukaryotic Cell, June 2004, p. 795-805, Vol. 3, No. 3
1535-9778/04/$08.00+0     DOI: 10.1128/EC.3.3.795-805.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Van Driessche, N., Alexander, H., Min, J., Kuspa, A., Alexander, S., Shaulsky, G. (2007). Global transcriptional responses to cisplatin in Dictyostelium discoideum identify potential drug targets. Proc. Natl. Acad. Sci. USA 104: 15406-15411 [Abstract] [Full Text]  
  • Min, J., Mesika, A., Sivaguru, M., Van Veldhoven, P. P., Alexander, H., Futerman, A. H., Alexander, S. (2007). (Dihydro)ceramide Synthase 1 Regulated Sensitivity to Cisplatin Is Associated with the Activation of p38 Mitogen-Activated Protein Kinase and Is Abrogated by Sphingosine Kinase 1. Mol Cancer Res 5: 801-812 [Abstract] [Full Text]  
  • Min, J., Van Veldhoven, P. P., Zhang, L., Hanigan, M. H., Alexander, H., Alexander, S. (2005). Sphingosine-1-Phosphate Lyase Regulates Sensitivity of Human Cells to Select Chemotherapy Drugs in a p38-Dependent Manner. Mol Cancer Res 3: 287-296 [Abstract] [Full Text]  
  • Min, J., Traynor, D., Stegner, A. L., Zhang, L., Hanigan, M. H., Alexander, H., Alexander, S. (2005). Sphingosine Kinase Regulates the Sensitivity of Dictyostelium discoideum Cells to the Anticancer Drug Cisplatin. Eukaryot Cell 4: 178-189 [Abstract] [Full Text]  


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