Altered sphingolipid metabolism in multidrug-resistant ovarian cancer cells is due to uncoupling of glycolipid biosynthesis in the Golgi apparatus

Autor: Jan Willem Kok, Hannie Sietsma, Karin Klappe, Gieta van der Schaaf, Robert Jan Veldman, John W.J. Hinrichs, Ina Hummel
Přispěvatelé: Groningen University Institute for Drug Exploration (GUIDE), Center for Liver, Digestive and Metabolic Diseases (CLDM)
Jazyk: angličtina
Rok vydání: 2002
Předmět:
Golgi Apparatus
ATP-binding cassette transporter
BREFELDIN-A
Biochemistry
GLYCOSPHINGOLIPID SYNTHESIS
chemistry.chemical_compound
glucosylceramide
PHOSPHATIDYLCHOLINE
Tumor Cells
Cultured
P-glycoprotein
SDZ PSC 833
Ovarian Neoplasms
music.instrument
MDR2 P-GLYCOPROTEIN
biology
Brefeldin A
brefeldin A
Galactosyltransferases
Drug Resistance
Multiple
gangliosides
Cell biology
symbols
Female
Sphingomyelin
Biotechnology
ATP Binding Cassette Transporter
Subfamily B
CELLULAR CERAMIDE FORMATION
Lactosylceramides
Galactosylceramides
Glucosylceramides
Models
Biological
Lactosylceramide
symbols.namesake
Glycolipid
Antigens
CD
Genetics
Animals
music
Molecular Biology
Sphingolipids
Carcinoma
Biological Transport
IN-VITRO
GLUCOSYLCERAMIDE SYNTHASE
Golgi apparatus
Sphingolipid
TRANSPORT
lactosylceramide
Kinetics
chemistry
Drug Resistance
Neoplasm
PLASMA-MEMBRANE
biology.protein
Glycolipids
Zdroj: The FASEB Journal, 16(7), 1111-+. FEDERATION AMER SOC EXP BIOL
ISSN: 0892-6638
Popis: Multidrug-resistant tumor cells display enhanced levels of glucosylceramide. In this study, we investigated how this relates to the overall sphingolipid composition of multidrug-resistant ovarian carcinoma cells and which mechanisms are responsible for adapted sphingolipid metabolism. We found in multidrug-resistant cells substantially lower levels of lactosylceramide and gangliosides in sharp contrast to glucosylceramide, galactosylceramide, and sphingomyelin levels. This indicates a block in the glycolipid biosynthetic pathway at the level of lactosylceramide formation, with concomitant accumulation of glucosylceramide. A series of observations exclude regulation at the enzyme level as the underlying mechanism. First, reduced lactosylceramide formation occurred only in intact resistant cells whereas cell-free activity of lactosylceramide synthase was higher compared with the parental cells. Second, the level of lactosylceramide synthase gene expression was equal in both phenotypes. Third, glucosylceramide synthase (mRNA and protein) expression and activity were equal or lower in resistant cells. Based on the kinetics of sphingolipid metabolism, the observation that brefeldin A does not restore lactosylceramide synthesis, and altered localization of lactosylceramide synthase fused to green fluorescent protein, we conclude that lactosylceramide biosynthesis is highly uncoupled from glucosylceramide biosynthesis in the Golgi apparatus of resistant cells.
Databáze: OpenAIRE
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