The absence of functional glucosylceramide synthase does not sensitize melanoma cells for anticancer drugs. FASEB J 2003 Jun;17(9):1144-6
Date
04/15/2003Pubmed ID
12692077DOI
10.1096/fj.02-1053fjeScopus ID
2-s2.0-0038380478 (requires institutional sign-in at Scopus site) 40 CitationsAbstract
Conversion of ceramide, a putative mediator of anticancer drug-induced apoptosis, into glucosylceramide, by the action of glucosylceramide synthase (GCS), has been implicated in drug resistance. Herein, we compared GM95 mouse melanoma cells deficient in GCS activity, with cells stably transfected with a vector encoding GCS (GM95/GCS). Enzymatic and metabolic analysis demonstrated that GM95/GCS cells expressed a fully functional enzyme, resulting in normal ceramide glycosylation. However, cytotoxicity assays, as well as caspase activation and cytochrome c release studies, did not reveal any difference between the two cell lines with respect to their sensitivity toward doxorubicin, vinblastine, paclitaxel, cytosine arabinoside, or short-chain ceramide analogs. Administration of doxorubicin resulted in ceramide accumulation in both cell lines, with similar kinetics and amplitude. Although glucosylceramide formation was detected in doxorubicin-treated GM95/GCS cells, metabolism of drug-induced ceramide did not appear to be instrumental in cell survival. Furthermore, N-(n-butyl)deoxynojirimycin, a potent and non-toxic GCS inhibitor, had no chemosensitizing effect on wild-type melanoma cells. Altogether, both genetic and pharmacological alterations of the cellular ceramide glycosylation capacity failed to sensitize melanoma cells to anticancer drugs, therefore moderating the importance of ceramide glucosylation in drug-resistance mechanisms.
Author List
Veldman RJ, Mita A, Cuvillier O, Garcia V, Klappe K, Medin JA, Campbell JD, Carpentier S, Kok JW, Levade TAuthor
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ATP-Binding Cassette TransportersAnimals
Antineoplastic Agents
Apoptosis
Cell Survival
Ceramides
Doxorubicin
Drug Resistance, Neoplasm
Gene Deletion
Glucosyltransferases
Melanoma, Experimental
Mice
Models, Biological
Transfection
Tumor Cells, Cultured
