Ceramide metabolism determines glioma cell resistance to chemotherapy.
Tumor cell resistance to chemotherapy constitutes a major problem in the treatment of malignant tumors. We here investigated the role of ceramide metabolism for the resistance of glioma cells to treatment with the chemotherapeutic drug, gemcitabine. Gemcitabine triggers a marked release of ceramide in drug-sensitive cells, while glioma cells that are resistant to gemcitabine, fail to accumulate ceramide. While the release of ceramide is very similar in gemcitabine-sensitive and resistant glioma cells upon stimulation, resistant glioma cells rapidly consume ceramide upon gemcitabine treatment or exogenous sphingomyelinase stimulation. Pharmacologic or genetic inhibition of glucosyltransferases prevents ceramide consumption in resistant cells and restores sensitivity of resistant glioma cells to gemcitabine. These data suggest that glioma cell resistance to at least some chemotherapeutic drugs is mediated by rapid consumption of ceramide to prevent cell death.
Dumitru
Claudia Alexandra
CA
Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
Weller
Michael
M
Gulbins
Erich
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism*; D005963:Glucosylceramides / Q000037:antagonists & inhibitors / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013107:Sphingolipids / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000093542:Gemcitabine
C095823:1-phenyl-2-palmitoylamino-3-morpholino-1-propanol; C494827:Bax protein, mouse; D002518:Ceramides; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D009025:Morpholines; D034741:RNA, Small Interfering; D013107:Sphingolipids; D051028:bcl-2-Associated X Protein; D003841:Deoxycytidine; D005964:Glucosyltransferases; D013108:Sphingomyelin Phosphodiesterase; D000093542:Gemcitabine