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Originally published In Press as doi:10.1194/jlr.M500070-JLR200 on September 8, 2005

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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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