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Changes in membrane microdomains and caveolae constituents in multidrug-resistant cancer cells

  • Phospholipases
  • Published:
Lipids

Abstract

Cancer chemotherapy often fails because of the development of tumors which are resistant to most commonly used cytotoxic drugs. This phenomenon, multidrug resistance (MDR), is usually mediated by overexpression of P-glycoprotein (P-gp), an ATPase that pumps out the drugs used in chemotherapy, thereby preventing their accumulation in cancer cells and greatly reducing their cytotoxic efficacy. A large body of work indicates that MDR is associated also with marked changes in membrane lipid composition. Most notably, elevated levels of cholesterol, glycosphingolipids (e.g., glucosylceramide), and sphingomyelin have been reported. These lipids are enriched in caveolae and in membrane microdomains termed detergent-insoluble glycosphingolipid-enriched complexes (DIGs). Recently we demonstrated that in multidrug-resistant tumor cells there is a dramatic increase in the number of caveolae and in the level of caveolin-1, an essential structural constituent of caveolae. Another constituent of membrane microdomains, phospholipase D, is also elevated in MDR cells. These findings may be related to the fact that a significant fraction of cellular P-gp is associated with caveolin-rich membrane domains. The possible role of DIGs and caveolae in the acquisition and/or maintenance of the multidrug resistant phenotype is discussed.

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Abbreviations

ABC:

ATP-binding cassette

DIGs:

detergent-insoluble glycosphingolipid-enriched complex

GlcCer:

glucosylceramide

MDR:

multidrug resistance

P-gp:

P-glycoprotein

PIP2 :

phosphatidylinositol 4,5-bisphosphate

PLD:

phospholipase D

SCRL:

sphingolipid- and cholesterol-rich liposome

SREBP:

sterol regulatory element-binding protein

References

  1. Gottesman, M.M. (1993) How Cancer Cells Evade Chemotherapy,Cancer Res. 53, 747–754.

    PubMed  CAS  Google Scholar 

  2. Kaye, S.B. (1995) Clinical Drug Resistance: The Role of Factors Other than P-glycoprotein,Am. J. Med. 99, 40S-44S.

    Article  PubMed  CAS  Google Scholar 

  3. Ford, J.M., and Hait, W.N. (1990) Pharmacology of Drugs That Alter Multidrug Resistance in Cancer,Pharmacol. Rev. 42, 155–199.

    PubMed  CAS  Google Scholar 

  4. Breuer, W., Slotki, I.N., Ausiello, D.A., and Cabantchik, I.Z. (1993) Induction of Multidrug Resistance Downregulates the Expression of CFTR in Colon Epithelial Cells,Am. J. Physiol. 265, C1711-C1715.

    PubMed  CAS  Google Scholar 

  5. Hansen, M.B., Nielsen, S.E., and Berg, K. (1989) Re-examination and Further Development of a Precise and Rapid Dye Method for Measuring Cell Growth/Cell Kill,J. Immunol. Meth. 119, 203–210.

    Article  CAS  Google Scholar 

  6. Bosch, I., and Croop, J. (1996) P-glycoprotein Multidrug Resistance and Cancer,Biochim. Biophys. Acta 1288, F37-F54.

    PubMed  Google Scholar 

  7. Borst, P. (1997) Introduction: Multidrug Resistant Proteins,Semin. Cancer Biol. 8, 131–134.

    Article  PubMed  CAS  Google Scholar 

  8. Deeley, R.G., and Cole, S.P.C. (1997) Function, Evolution and Structure of Multidrug Resistance Protein (MRP),Semin. Cancer Biol. 8, 193–204.

    Article  PubMed  CAS  Google Scholar 

  9. Montaudon, D., Vrignaud, P., Londos-Gagliardi, D., and Robert, J. (1986) Fluorescence Anisotropy of Cell Membranes of Doxorubicin-Sensitive and -Resistant Rodent Tumoral Cells,Cancer Res. 46, 5602–5605.

    PubMed  CAS  Google Scholar 

  10. Tritton, T.R., and Yee, G. (1982) The Anticancer Agent Adriamycin Can Be Actively Cytotoxic Without Entering Cells,Nature 217, 248–250.

    CAS  Google Scholar 

  11. Leibovici, J., Klein, O., Wollman, Y., Donin, N., Mahlin, T., and Shinitzky, M. (1996) Cell Membrane Fluidity and Adriamycin Retention in a Tumor Progression Model of AKR Lymphoma,Biochim. Biophys. Acta 1281, 182–188.

    Article  PubMed  Google Scholar 

  12. Higgins, C.F., and Gottesman, M.M. (1992) Is the Multidrug Transporter a Flippase?Trends Biochem. Sci. 17, 18–21.

    Article  PubMed  CAS  Google Scholar 

  13. Higgins, C.F., Callaghan, R., Linton, K.J., Rosenberg, M.F., and Ford, R.C. (1997) Structure of the Multidrug Resistance P-glycoprotein,Semin. Cancer Biol. 8, 135–142.

    Article  PubMed  CAS  Google Scholar 

  14. Doige, C.A., Yu, X., and Sharom, F.J. (1993) The Effects of Lipids and Detergents on ATPase-Active P-glycoprotein,Biochim. Biophys. Acta 1146, 65–72.

    Article  PubMed  CAS  Google Scholar 

  15. Urbatsch, I.L., and Senior, A.E. (1995) Effects of Lipids on ATPase Activity of Purified Chinese Hamster P-glycoprotein,Arch. Biochem. Biophys. 316, 135–140.

    Article  PubMed  CAS  Google Scholar 

  16. Vrignaud, P., Montaudon, D., Londos-Gagliardi, D., and Robert, J. (1986) Fatty Acid Composition Transport and Metabolism in Doxorubicin-Sensitive and -Resistant Rat Glioblastoma Cells,Cancer Res. 46, 3258–3261.

    PubMed  CAS  Google Scholar 

  17. Ramu, A., Glaubiger, D., and Weintraub, H. (1984) Differences in Lipid Composition of Doxorubicin-Sensitive and -Resistant P388 Cells,Cancer Treat. Rep. 68, 637–641.

    PubMed  CAS  Google Scholar 

  18. Lavie, Y., Cao, H.-T., Bursten, S.L., Giuliano, A.E., and Cabot, M.C. (1996) Accumulation of Glucosylceramides in Multidrug-Resistant Cancer Cells,J. Biol. Chem. 271, 19530–19536.

    Article  PubMed  CAS  Google Scholar 

  19. May, G.L., Wright, L.C., Dyne, M., Mackinnon, W.B., Fox, R.M., and Mountford, C.E. (1988) Plasma Membrane Lipid Composition of Vinblastine Sensitive and Resistant Human Leukaemic Lymphoblasts,Int. J. Cancer 42, 728–733.

    PubMed  CAS  Google Scholar 

  20. Hakomori, S.-I. (1993) Structure and Function of Sphingoglycolipids in Transmembrane Signalling and Cell-Cell Interactions,Biochem. Soc. Trans. 21, 583–595

    PubMed  CAS  Google Scholar 

  21. Peterson, R.H., Meyers, M.B., Spengler, B.A., and Biedler, J.L. (1983) Alteration of Plasma Membrane Glycopeptides and Gangliosides of Chinese Hamster Cells Accompanying Development of Resistance to Daunorubicin and Vincristine,Cancer Res. 43, 222–228.

    PubMed  CAS  Google Scholar 

  22. Mountford, C.E., and Wright, L.C. (1988) Organization of Lipids in the Plasma Membranes of Malignant and Stimulated Cells: A New Model,Trends Biochem. Sci. 13, 172–177.

    Article  PubMed  CAS  Google Scholar 

  23. Mazzoni, A., and Trave, F. (1993) Cytoplasmic Membrane Cholesterol and Doxorubicin Cytotoxicity in Drug-Sensitive and Multidrug-Resistant Human Ovarian Cancer Cells,Oncol. Res. 5, 75–82.

    PubMed  CAS  Google Scholar 

  24. Brown, D.A., and London, E. (1997) Structure of Detergent-Resistant Membrane Domains: Does Phase Separation Occur in Biological Membranes?Biochem. Biophys. Res. Commun. 240, 1–7.

    Article  PubMed  CAS  Google Scholar 

  25. Brown, D.A., and London, E. (1998) Structure and Origin of Ordered Lipid Domains in Biological Membranes,J. Membr. Biol. 164, 103–114.

    Article  PubMed  CAS  Google Scholar 

  26. Parton, R.G., and Simons, K. (1995) Digging into Caveolae,Science 269, 1398–1399.

    Article  PubMed  CAS  Google Scholar 

  27. Rodgers, W., Crise, B., and Rose, J.K. (1994) Signals Determining Protein Tyrosine Kinase and Glycosyl-Phosphatidylinositol-Anchored Protein Targeting to a Glycolipid-Enriched Membrane Fraction,Mol. Cell. Biol. 14, 5384–5391.

    PubMed  CAS  Google Scholar 

  28. Parolini, I., Sargiacomo, M., Lisanti, M.P., and Peschle, C. (1996) Signal Transduction and Glycophosphatidylinositol-Linked Proteins (lyn, lck, CD4, CD45, G proteins, and CD55) Selectively Localize in Triton-Insoluble Plasma Membrane Domains of Human Leukemic Cell Lines and Normal Granulocytes,Blood 87, 3783–3794.

    PubMed  CAS  Google Scholar 

  29. Simons, K., and Ikonen, E. (1997) Functional Rafts in Cell Membranes,Nature 387, 569–572.

    Article  PubMed  CAS  Google Scholar 

  30. Brown, D., and Rose, J.K. (1992) Sorting of GPI-Anchored Proteins to Glycolipid-Enriched Membrane Subdomains During Transport to the Apical Cell Surface,Cell 68, 533–544.

    Article  PubMed  CAS  Google Scholar 

  31. Schroeder, R., London, E., and Brown, D. (1994) Interactions Between Saturated Acyl Chains Confer Detergent Resistance on Lipids and Glycosylphosphatidylinositol (GPI)-Anchored Proteins: GPI-Anchored Proteins in Liposomes and Cells Show Similar Behavior,Proc. Natl. Acad. Sci. USA 91, 12130–12134.

    Article  PubMed  CAS  Google Scholar 

  32. Schroeder, R.J., Ahmed, S.N., Zhu, Y., London, E., and Brown, D.A. (1998) Cholesterol and Sphingolipid Enhance the Triton X-100 Insolubility of Glycosylphosphatidylinositol-Anchored Proteins by Promoting the Formation of Detergent-Insoluble Ordered Membrane Domains,J. Biol. Chem. 273, 1150–1157.

    Article  PubMed  CAS  Google Scholar 

  33. Iwabuchi, K., Yamamura, S., Prinetti, A., Handa, K., and Hakomori, S. (1998) GM3-Enriched Microdomain Involved in Cell Adhesion and Signal Transduction Through Carbohydrate-Carbohydrate Interaction in Mouse Melanoma B16 Cells,J. Biol. Chem. 273, 9130–9138.

    Article  PubMed  CAS  Google Scholar 

  34. Okamoto, T., Schlegel, A., Scherer, P.E., and Lisanti, M.P. (1998) Caveolins, a Family of Scaffolding Proteins for Organizing “Preassembled Signaling Complexes” at the Plasma Membrane,J. Biol. Chem. 273, 5419–5422.

    Article  PubMed  CAS  Google Scholar 

  35. Harder, T., and Simons, K. (1997) Caveolae, DIGs, and the Dynamics of Sphingolipid-Cholesterol Microdomains,Curr. Opin. Cell Biol. 9, 534–542.

    Article  PubMed  CAS  Google Scholar 

  36. Severs, N.J. (1988) Caveolae: Static Inpocketings of the Plasma Membrane, Dynamic Vesicles or Plain Artifact?J. Cell Sci. 90, 341–348.

    PubMed  Google Scholar 

  37. Rothberg, K.G., Heuser, J.E., Donzell, W.C., Ying, Y.S., Glenney, J.R., and Anderson, R.G. (1992) Caveolin, a Protein Component of Caveolae Membrane Coats,Cell 68, 673–682.

    Article  PubMed  CAS  Google Scholar 

  38. Parton, R.G. (1996) Caveolae and Caveolins,Curr. Opin. Cell Biol. 8, 542–548.

    Article  PubMed  CAS  Google Scholar 

  39. Lisanti, M.P., Tang, Z., Scherer, P.E., and Sargiacomo, M. (1995) Caveolae Purification and Glycosylphosphatidylinositol-linked Protein Sorting in Polarized Epithelia,Meth. Enzymol. 250, 655–668.

    Article  PubMed  CAS  Google Scholar 

  40. Oh, P., McIntosh, D.P., and Schnitzer, J.E. (1998) Dynamin at the Neck of Caveolae Mediates Their Budding to Form Transport Vesicles by GTP-Driven Fission from the Plasma Membrane of Endothelium,J. Cell Biol. 141, 101–114.

    Article  PubMed  CAS  Google Scholar 

  41. Fielding, C.J., and Fielding, P.E. (1997) Intracellular Cholesterol Transport,J. Lipid Res. 38, 1503–1521.

    PubMed  CAS  Google Scholar 

  42. Lisanti, M.P., Tang, Z., Scherer, P.E., Kubler, E., Koleske, A.J., and Sargiacomo, M. (1995) Caveolae, Transmembrane Signalling and Cellular Transformation,Mol. Memb. Biol. 12, 121–124.

    CAS  Google Scholar 

  43. Lavie, Y., and Liscovitch, M. (1997) A Role for Caveolae in Multidrug Resistance of Cancer Cells,Mol. Biol. Cell 8, 207a.

    Google Scholar 

  44. Lavie, Y., Fiucci, G. and Liscovitch, M. (1998) Up-regulation of Caveolae and Caveolar Constituents in Multidrug Resistant Cancer Cells,J. Biol. Chem. 273, 32380–32383.

    Article  PubMed  CAS  Google Scholar 

  45. Pike, L.J., and Casey, L. (1996) Localization and Turnover of Phosphatidylinositol 4,5-Bisphosphate in Caveolin-Enriched Membrane Domains,J. Biol. Chem. 271, 26453–26456.

    Article  PubMed  CAS  Google Scholar 

  46. Hope, H.R., and Pike, L.J. (1996) Phosphoinositides and Phosphoinositide-Utilizing Enzymes in Detergent-Insoluble Lipid Domains,Mol. Biol. Cell 7, 843–851.

    PubMed  CAS  Google Scholar 

  47. Liu, J., Oh, P., Horner, T., Rogers, R.A., and Schnitzer, J.E. (1997) Organized Endothelial Cell Surface Signal Transduction in Caveolae Distinct from Glycosylphosphatidylinositol-Anchored Protein Microdomains,J. Biol. Chem. 272, 7211–7222.

    Article  PubMed  CAS  Google Scholar 

  48. Waugh, M.G., Lawson, D., Tan, S.K., and Hsuan, J.J. (1998) Phosphatidylinositol 4-Phosphate Synthesis in Immunoisolated Caveolae-Like Vesicles and Low Buoyant Density Non-caveolar Membranes,J. Biol. Chem. 273, 17115–17121.

    Article  PubMed  CAS  Google Scholar 

  49. Liu, Y., Casey, L., and Pike, L.J. (1998) Compartmentalization of Phosphatidylinositol 4,5-Bisphosphate in Low-Density Membrane Domains in the Absence of Caveolin,Biochem. Biophys. Res. Commun. 245, 684–690.

    Article  PubMed  CAS  Google Scholar 

  50. Liscovitch, M., Chalifa, V., Pertile, P., Chen, C.-S., and Cantley, L.C. (1994) Novel Function of Phosphatidylinositol 4,5-Bisphosphate as a Cofactor for Brain Membrane Phospholipase D,J. Biol. Chem. 269, 21403–21406.

    PubMed  CAS  Google Scholar 

  51. Brown, H.A., Gutowski, S., Moomaw, C.R., Slaughter, C., and Sternweis, P.C. (1993) ADP-Ribosylation Factor, a Small GTP-Dependent Regulatory Protein, Stimulates Phospholipase D Activity,Cell 75, 1137–1144.

    Article  PubMed  CAS  Google Scholar 

  52. Yokozeki, T., Kuribara, H., Katada, T., Touhara, K., and Kanaho, Y. (1996) Partially Purified RhoA-Stimulated Phospholipase D Activity Specifically Binds to Phosphatidylinositol 4,5-Bisphosphate,J. Neurochem. 66, 1234–1239.

    Article  PubMed  CAS  Google Scholar 

  53. Kim, J.H., Lee, S.D., Han, J.M., Lee, T.G., Kim, Y., Park, J.B., Lambeth, J.D., Suh, P.G., and Ryu, S.H. (1998) Activation of Phospholipase D1 by Direct Interaction with ADP-Ribosylation Factor 1 and RalA,FEBS Lett. 430, 231–235.

    Article  PubMed  CAS  Google Scholar 

  54. Lavie, Y., Czarny, M., and Liscovitch, M. (1997) Localization of Phospholipase D in Caveolae and Its Up-regulation in Multidrug Resistant Cancer Cells,FASEB J. 11, A1346.

  55. Czarny, M., Lavie, Y., Fiucci, G. and Liscovitch, M. (1999) Localization of Phospholipase D in Detergent-Insoluble, Caveolin-Rich Membrane Domains. Modulation by Caveolin-1 Expression and Caveolin-182-101,J. Biol. Chem. 274, 2717–2724.

    Article  PubMed  CAS  Google Scholar 

  56. Fielding, P.E., and Fielding, C.J. (1995) Plasma Membrane Caveolae Mediate the Efflux of Cellular Free Cholesterol,Biochemistry 34, 14288–14292.

    Article  PubMed  CAS  Google Scholar 

  57. Fielding, P.E., and Fielding, C.J. (1996) Intracellular Transport of Low Density Lipoprotein Derived Free Cholesterol Begins at Clathrin-Coated Pits and Terminates at Cell Surface Caveolae,Biochemistry 35, 14932–19438.

    Article  PubMed  CAS  Google Scholar 

  58. Fielding, C.J., Bist, A., and Fielding, P.E. (1997) Caveolin mRNA Levels Are Up-regulated by Free Cholesterol and Downregulated by Oxysterols in Fibroblast Monolayers,Proc. Natl. Acad. Sci. USA 94, 3753–3758.

    Article  PubMed  CAS  Google Scholar 

  59. Bist, A., Fielding, P.E., and Fielding, C.J. (1997) Two Sterol Regulatory Element-like Sequences Mediate Up-regulation of Caveolin Gene Transcription in Response to Low Density Lipoprotein Free Cholesterol,Proc. Natl. Acad. Sci. USA 94, 10693–10698.

    Article  PubMed  CAS  Google Scholar 

  60. Brown, M.S., and Goldstein, J.L. (1997) The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor,Cell 89, 331–340.

    Article  PubMed  CAS  Google Scholar 

  61. Koleske, A.J., Baltimore, D., and Lisanti, M.P. (1995) Reduction of Caveolin and Caveolae in Oncogenically Transformed Cells,Proc. Natl. Acad. Sci. USA 92, 1381–1385.

    Article  PubMed  CAS  Google Scholar 

  62. Engelman, J.A., Wykoff, C.C., Yasuhara, S., Song, K.S., Okamoto, T., and Lisanti, M.P. (1997) Recombinant Expression of Caveolin-1 in Oncogenically Transformed Cells Abrogates Anchorage-Independent Growth,J. Biol. Chem. 272, 16374–16381.

    Article  PubMed  CAS  Google Scholar 

  63. Lee, S.W., Reimer, C.L., Oh, P., Campbell, D.B., and Schnitzer, J.E. (1998) Tumor Cell Growth Inhibition by Caveolin Re-expression in Human Breast Cancer Cells,Oncogene 16, 1391–1397.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Biological Regulation, Weizmann Institute of Science, 76100, Rehovot, Israel

    Yaakov Lavie, Giusy Fiucci, Malgorzata Czarny & Mordechai Liscovitch

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  1. Yaakov Lavie
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  2. Giusy Fiucci
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  3. Malgorzata Czarny
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  4. Mordechai Liscovitch
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Correspondence to Mordechai Liscovitch.

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Lavie, Y., Fiucci, G., Czarny, M. et al. Changes in membrane microdomains and caveolae constituents in multidrug-resistant cancer cells. Lipids 34 (Suppl 1), S57–S63 (1999). https://doi.org/10.1007/BF02562229

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