Caveolin-1 is a major caveolae-coat protein involved in a variety of cell signaling processes. Some studies have suggested that the level of caveolin-1 expression positively correlates with multi-drug resistance in cancer cells. We demonstrated for the first time that Hs578T doxorubicin resistant cells (Hs578T/Doxo), which contain low levels of endogenous caveolin-1 and high levels of P-glycoprotein, are rendered drug-sensitive by overexpression of exogenous caveolin-1. MTT assays showed that after overexpressing caveolin-1, the drug resistance of Hs578T/Doxo cells to doxorubicin and cisplatin was reduced from 25.4 +/- 1.5 and 65.3 +/- 2.5 microg/ml to 0.8 +/- 0.15 and 23.2 +/- 2.1 microg/ml, respectively (i.e. reduced by 97% and 64%, respectively). Furthermore, using rhodamine-123 efflux assays, we observed a significant decrease in P-glycoprotein activity in caveolin-1 overexpressing cells, similar to that observed with 5 microM cyclosporine A or 10 microM verapamil, 2 inhibitors of P-glycoprotein activity. Using confocal microscopy, subcellular fractionation and co-immunoprecipitation assays, a possible physical interaction between caveolin-1 and P-glycoprotein in the caveolae membrane was observed in Hs578T/Doxo cells overexpressing caveolin-1. These results suggest that overexpression of caveolin-1 changes the state of the cells from drug-resistant to drug-sensitive by inhibiting P-glycoprotein transport activity.
Copyright 2004 Wiley-Liss, Inc.