Yang C P, Galbiati F, Volonte D, Horwitz S B, Lisanti M P
Department of Molecular Pharmacology and The Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
FEBS Lett. 1998 Nov 20;439(3):368-72. 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 SKVLBI 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.
小窝蛋白是小窝膜的主要成分。已证明小窝蛋白支架结构域与信号分子的相互作用可在功能上抑制这些分子的活性。紫杉醇是一种抗肿瘤药物，它能抑制微管动力学并与微管结合，从而使其稳定以防止解聚。该药物还与通过激活信号转导级联反应中的成分诱导细胞凋亡有关。在此，我们通过检测小窝蛋白在低水平和高水平耐药细胞系中的表达，研究了小窝蛋白在耐药性发展中的作用。在高度多药耐药的SKVLBI细胞（其表达高水平的P-糖蛋白）以及低水平紫杉醇耐药的A549细胞系（其表达少量的P-糖蛋白）中，小窝蛋白-1而非小窝蛋白-2的表达上调。两种耐药的A549细胞系（一种对紫杉醇耐药9倍，另一种对埃坡霉素B耐药1.5倍），二者均不表达P-糖蛋白，显示小窝蛋白-1的表达显著增加。这些结果表明，在低水平埃坡霉素B或紫杉醇耐药的A549细胞中，小窝蛋白-1表达的增加独立于P-糖蛋白的表达。电子显微镜研究清楚地证明了紫杉醇耐药的A549细胞中小窝细胞器的上调。在用10 nM紫杉醇孵育48小时后，在药物敏感的A549细胞中急性观察到小窝蛋白-1表达的上调。因此，小窝蛋白-1可能在A549细胞中紫杉醇耐药性的发展中起作用。
