Upregulation of caveolin-1 and caveolae organelles in Taxol-resistant A549 cells

• Published in: FEBS letters 1998-11, Vol.439 (3), p.368-372
• Main Authors: Yang, Chia-Ping Huang, Galbiati, Ferruccio, Volonté, Daniela, Horwitz, Susan Band, Lisanti, Michael P
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents, Phytogenic - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - biosynthesis; Caveolae; Caveolin; Caveolin 1; Caveolins; Drug resistance; Drug Resistance, Neoplasm; Epothilones; Epoxy Compounds - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Humans; MAP kinase, mitogen-activated protein kinase; MDR, multidrug resistance; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Organelles - drug effects; Organelles - metabolism; P-glycoprotein; Paclitaxel - pharmacology; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; Taxol; Thiazoles - pharmacology; TNF-α, tumor necrosis factor α; Tumor Cells, Cultured; Up-Regulation
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(98)01354-4

Caveolin is a principal component of caveolae membranes. It has been demonstrated that the interaction of the caveolin scaffolding domain with signaling molecules can functionally inhibit the activity of these molecules. Taxol is an antitumor agent that suppresses microtubule dynamics and binds to microtubules thereby stabilizing them against depolymerization. The drug also has been implicated in the induction of apoptosis through activation of components in signal transduction cascades. Here we have investigated the role of caveolin in the development of 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 express high levels of P-glycoprotein, and in low-level Taxol-resistant A549 cell lines that express low amounts of P-glycoprotein. Two drug-resistant 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-glycoprotein, demonstrate a significant increase in the expression of caveolin-1. These results indicate that in low-level epothilone B- or Taxol-resistant A549 cells, increased caveolin-1 expression occurs independently 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 A549 cells was observed acutely beginning 48 h after incubation with 10 nM Taxol. Thus, caveolin-1 may play a role in the development of Taxol resistance in A549 cells.