UP-REGULATION OF CAVEOLIN-1 AND CAVEOLAE ORGANELLES IN TAXOL-RESISTANT A549 CELLS

Caveolin is a principal component of caveolae membranes. It has been d emonstrated that the interaction of the caveolin scaffolding domain wi th signaling molecules can functionally inhibit the activity of these molecules, Taxol is an antitumor agent that suppresses microtubule dyn amics and binds to microtubules thereby stabilizing them against depol ymerization, The drug also has been implicated in the induction of apo ptosis through activation of components in signal transduction cascade s. Here me have investigated the role of caveolin in the development o f drug resistance by examining the expression of caveolins in low- and high-level drug-resistant cell lines. Caveolin-1, but not caveolin-2, was upregulated in highly multidrug resistant SKVLB1 cells that expre ss high levels of P-glycoprotein, and in low-level Taxol-resistant A53 9 cell lines that express ion amounts of P-glycoprotein. Two drug-resi stant A549 cell lines (one 9-fold resistant to Taxol and the other 1.5 -fold resistant to epothilone B), both of which express no P-gly copro tein, demonstrate a significant increase in the expression of caveolin -1, These results indicate that in low-level epothilone B- or Taxol-re sistant A549 cells, increased caveolin-1 expression occurs independent ly of P-glycoprotein expression, Electron microscopic studies clearly demonstrate the upregulation of caveolae organelles in Taxol-resistant A549 cells. Upregulation of caveolin-1 expression in drug-sensitive A 519 cells,vas observed acutely beginning 48 h after incubation with 10 nM Taxol, Thus, caveolin-1 may play a role in the development of Taxo l resistance in A519 cells. (C) 1998 Federation of European Biochemica l Societies.