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Journal of Lipid Research, Vol. 46, 2367-2376, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Drug resistance-associated changes in sphingolipids and ABC transporters occur in different regions of membrane domains

John W. J. Hinrichs, Karin Klappe, Manon van Riezen and Jan W. Kok¹

Department of Cell Biology, Section of Membrane Cell Biology, University Medical Center Groningen, Groningen, The Netherlands

Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500070-JLR200

¹ To whom correspondence should be addressed. e-mail: j.w.kok{at}med.umcg.nl

We have recently shown that two ATP binding cassette (ABC) transporters are enriched in Lubrol-resistant noncaveolar membrane domains in multidrug-resistant human cancer cells [Hinrichs, J. W. J., K. Klappe, I. Hummel, and J. W. Kok. 2004. ATP-binding cassette transporters are enriched in non-caveolar detergent-insoluble glycosphingolipid-enriched membrane domains (DIGs) in human multidrug-resistant cancer cells. J. Biol. Chem. 279: 5734–5738]. Here, we show that aminophospholipids are relatively enriched in Lubrol-resistant membrane domains compared with Triton X-100-resistant membrane domains, whereas sphingolipids are relatively enriched in the latter. Moreover, Lubrol-resistant membrane domains contain more protein and lipid mass. Based on these results, we postulate a model for detergent-insoluble glycosphingolipid-enriched membrane domains consisting of a Lubrol-insoluble/Triton X-100-insoluble region and a Lubrol-insoluble/Triton X-100-soluble region. The latter region contains most of the ABC transporters as well as lipids known to be necessary for their efflux activity. Compared with drug-sensitive cells, the detergent-insoluble glycosphingolipid-enriched membrane domains (DIGs) in drug-resistant cells differ specifically in sphingolipid content and not in protein, phospholipid, or cholesterol content. In drug-resistant cells, sphingolipids with specific fatty acids (especially C24:1) are enriched in these membrane domains.

Together, these data show that multidrug resistance-associated changes in both sphingolipids and ABC transporters occur in DIGs, but in different regions of these domains.

Abbreviations: ABC, ATP binding cassette; DIG, detergent-insoluble glycosphingolipid-enriched membrane domain; ESI-MS/MS, liquid chromatography-electrospray tandem mass spectrometry; GlcCer, glucosylceramide; HPTLC, high-performance thin-layer chromatography; LacCer, lactosylceramide; MDR, multidrug resistance; MRP, multidrug resistance-associated protein; PC, phosphatidylcholine; PE, phosphatidylethanolamine; Pgp, P-glycoprotein; PS, phosphatidylserine; SM, sphingomyelin; TNE, Tris-NaCl-EDTA buffer

Supplementary key words P-glycoprotein • multidrug resistance protein 1 • glucosylceramide • C24:1 fatty acid • aminophospholipids • liquid chromatography-electrospray tandem mass spectrometry • ATP binding cassette transporters

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