Submitted on February 22, 2005
Revised on July 28, 2005
Accepted on August 18, 2005
Detergent-insoluble glycosphingolipid-enriched membrane domains in drug-resistant cancer cells are enriched in specific sphingolipids and ATP binding cassette transporters in different regions of these domains
John W.J. Hinrichs, Karin Klappe, Manon van Riezen, and Jan W. Kok
Cell Biology, section Membrane Cell Biology, University Medical Center Groningen, Groningen 9713 AV
Corresponding Author: j.w.kok{at}med.umcg.nl
We have recently shown that two ATP-binding cassette transporters are enriched in Lubrol resistant non-caveolar membrane domains in multidrug resistant human cancer cells (Hinrichs, J. W. J., Klappe, K., Hummel, I., and Kok, J. W. (2004) J. Biol. Chem. 279, 5734-5738). Here we show that aminophospholipids are relatively enriched in Lubrol resistant membrane domains compared to Triton X-100 resistant membrane domains, while 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 and a Lubrol insoluble/Triton X-100 soluble region. The latter region contains most of the ATP-binding cassette transporters as well as lipids known to be necessary for their efflux activity. When compared to drug-sensitive cells, the detergent-insoluble glycosphingolipid-enriched membrane domains 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 sphingolipids and ATP-binding cassette transporters both occur in detergent-insoluble glycosphingolipid-enriched membrane domains, but in different regions of these domains.
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