Up-regulation of caveolae and caveolar constituents in multidrug-resistantcancer cells

Cancer chemotherapy often results in the development of multidrug resistanc e (MDR), which is commonly associated with overexpression of P-glycoprotein (P-gp), a plasma membrane drug efflux ATPase, It was shown recently that g lycosphingolipids are elevated in MDR cells. Sphingolipids are major consti tuents of caveolae and of detergent-insoluble, glycosphingolipid-rich membr ane domains. Here we report that multidrug-resistant HT-29 human colon aden ocarcinoma cells exhibit a 12-fold overexpression of caveolin-1, a 21-kDa c oat/adaptor protein of caveolae, Similar observations were made in adriamyc in-resistant MCF-7 human breast adenocarcinoma cells. Caveolin-2 expression is also up-regulated in MCF-7-AdrR cells, but neither caveolin-l nor caveo lin-2 were detected in MCF-7 cells stably transfected with P-gp, The up-reg ulation 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-A drR cells, A significant fraction (similar to 40%) of cellular P-gp is loca lized in low density detergent-insoluble membrane fractions derived from ei ther HT-29-RIDR or MCF-7-AdrR cells. The distribution of recombinant P-gp i n stably transfected MCF-7 cells was similar, even though these cells do no t express caveolins and are devoid of caveolae. The possibility that caveol ae contribute to the multidrug resistance and thus are coselected with P-gp during the acquisition of this phenotype is discussed.