Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells.
Previously we demonstrated that multidrug-resistant (MDR) cancer cells have elevated levels of a glycosylated form of ceramide, glucosylceramide. Here we compared ceramide metabolism and ceramide toxicity in MCF-7 and in adriamycin-resistant (MCF-7-AdrR) human breast cancer cells. MCF-7-AdrR cells were resistant to C6-ceramide (1-10 microM); however, in MCF-7 cells treated with C6-ceramide, viability dropped sharply. Ceramide, when supplemented, was not metabolized by MCF-7 cells. In contrast, ceramide was efficiently converted to glucosylceramide by MCF-7-AdrR cells. Analysis of extracellular [3H]ceramide in radiolabeled cells showed that MCF-7-AdrR cells do not have an enhanced capacity to efflux ceramide compared with MCF-7 cells. Triphenylethylene anti-estrogens, known modulators of drug resistance, were effective inhibitors of ceramide conversion to glucosylceramide, suggesting that blocking ceramide metabolism plays a role in chemosensitization. The anti-progestine, RU486, also blocked glucosylceramide synthesis in cells; however, LY117018, a raloxifene analog, was without influence. We propose that an enhanced capacity to glycosylate ceramide as evidenced in MCF-7-AdrR cells, is a molecular determinant of drug resistance, particularly as regards resistance to ceramide-enhancing agents such as anthracyclines, ionizing radiation, and tumor necrosis factor-alpha.
Lucci
A
A
John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA.
Giuliano
A E
AE
Han
T Y
TY
Dinur
T
T
Liu
Y Y
YY
Senchenkov
A
A
Cabot
M C
MC
D002518:Ceramides / Q000633:toxicity*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D004965:Estrogen Antagonists / Q000627:therapeutic use; D006727:Hormone Antagonists / Q000627:therapeutic use; D006801:Humans; D015735:Mifepristone / Q000627:therapeutic use; D010641:Phenotype; D011372:Progestins / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D002518:Ceramides; D004965:Estrogen Antagonists; D006727:Hormone Antagonists; D011372:Progestins; D015735:Mifepristone