RRC ID 28720
Author Min J, Stegner AL, Alexander H, Alexander S.
Title 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.
Journal Eukaryot Cell
Abstract 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.
Volume 3(3)
Pages 795-805
Published 2004-6-1
DOI 10.1128/EC.3.3.795-805.2004
PII 3/3/795
PMID 15190000
PMC PMC420124
MeSH Aldehyde-Lyases / metabolism* Animals Carboplatin / pharmacology* Cell Death / drug effects Cell Enlargement / drug effects Cell Nucleus / drug effects Cell Nucleus / metabolism Ceramides / pharmacology Cisplatin / pharmacology* Cloning, Molecular Dictyostelium / cytology Dictyostelium / drug effects Dictyostelium / metabolism* Doxorubicin / pharmacology Enzyme Inhibitors / pharmacology Fluorouracil / pharmacology Mutation / genetics Parasitic Sensitivity Tests Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors Phosphotransferases (Alcohol Group Acceptor) / metabolism* Sphingolipids / metabolism Sphingosine / analogs & derivatives Sphingosine / pharmacology
IF 2.992
Times Cited 39
Cellular slime molds