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

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.