Journal of Biological Chemistry
Volume 273, Issue 49, 4 December 1998, Pages 32380-32383
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Up-regulation of Caveolae and Caveolar Constituents in Multidrug-resistant Cancer Cells*

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Cancer chemotherapy often results in the development of multidrug resistance (MDR), which is commonly associated with overexpression of P-glycoprotein (P-gp), a plasma membrane drug efflux ATPase. It was shown recently that glycosphingolipids are elevated in MDR cells. Sphingolipids are major constituents of caveolae and of detergent-insoluble, glycosphingolipid-rich membrane domains. Here we report that multidrug-resistant HT-29 human colon adenocarcinoma cells exhibit a 12-fold overexpression of caveolin-1, a 21-kDa coat/adaptor protein of caveolae. Similar observations were made in adriamycin-resistant MCF-7 human breast adenocarcinoma cells. Caveolin-2 expression is also up-regulated in MCF-7-AdrR cells, but neither caveolin-1 nor caveolin-2 were detected in MCF-7 cells stably transfected with P-gp. The up-regulation of caveolins is associated with a 5-fold increase in the number of caveolae-like structures observed in plasma membrane profiles of HT-29-MDR cells and with the appearance of a comparable number of caveolae in MCF-7-AdrR cells. A significant fraction (∼40%) of cellular P-gp is localized in low density detergent-insoluble membrane fractions derived from either HT-29-MDR or MCF-7-AdrR cells. The distribution of recombinant P-gp in stably transfected MCF-7 cells was similar, even though these cells do not express caveolins and are devoid of caveolae. The possibility that caveolae contribute to the multidrug resistance and thus are co-selected with P-gp during the acquisition of this phenotype is discussed.

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Incumbent of the Harold L. Korda Professorial Chair in Biology.

*

This work was supported in part by grants from the H. Levine Fund and the Forchheimer Center for Molecular Genetics (Rehovot).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a grant-in-aid from the Israel Ministry of Absorption.