Upregulation of caveolin in multidrug resistant cancer cells: functional implications

Multidrug resistance (MDR) is a multifactorial process that involves elevat ed expression of drug transporters as well as additional biochemical change s that contribute to the drug resistant phenotype. Here we review recent re sults indicating the upregulation of constituents of rafts and caveolae, in cluding glucosylceramide, cholesterol and caveolin-1, in MDR cells. Accordi ngly, the number of plasma membrane caveolae is greatly increased in MDR ce lls. The relationship between caveolin and MDR may be linked to the functio n of caveolin-1 in mediating cholesterol efflux, a pathway that we hypothes ized to facilitate the delivery of drugs from intracellular compartments to plasma membrane resident drug transporters. An additional link seems to ex ist between the upregulation of GlcCer synthase and attenuation of ceramide -mediated apoptotic signaling. These adaptations may promote cell survival during chemotherapy and, hence, would be positively selected during cell ex posure to cytotoxic drugs. However, the overexpression of caveolin-1, an on cosuppressive protein, may also reverse or attenuate important aspects of t he phenotypic transformation of MDR cells. The molecular mechanisms by whic h caveolin-1 exerts its effects on cell proliferation, cell survival, and m ultidrug resistance remain to be fully elucidated. (C) 2001 Elsevier Scienc e B.V. All rights reserved.