Caveolae resistance

Carcinogenesis involves a complex series of genetic and biochemical events that enable transformed cells to proliferate, metastasize, migrate to secondary sites, and, sometimes, acquire resistance to chemotherapy. In Sect. 25.4.1, we will discuss how caveolin-1 expression correlates with cancerous growth, a potential mechanism of chemotherapy drug resistance, and how caveolae may be particularly exploited for cancer therapeutic strategies. 

In MDR cells, a significant fraction of P-gp is found associated with caveolin-rich membranes, and there is a substantial increase in the number of caveolae and caveolin-1 protein level. For example, both multidrug resistant human colon adenocarcinoma HT-29 cells and adriamycin-resistant breast adenocarcinoma MCF-7 cells display about a 12-fold increase in caveolin expression, which correlates with an approximate fivefold increase in morphologically identifiable caveolae [55], In addition, these cells exhibit increased amounts of phospholipase D and lipids such as cholesterol, glucosylceramide, and sphingomyelin [56, 57], Similarly, taxol-resistant A549 cells display both increased caveolin expression and caveolae numbers [58], While these correlations track with MDR, they do not suggest a simple mechanism for the role of... 

Y. Lavie, G. Fiucci, and M. Liscovitch. Up-regulation of caveolae and caveloar constituents in multidrug-resistant cancer cells. J. Biol. Chem. 213. 32380-32383 (1998). 

Y. Lavie and M. Liscovitch. Changes in lipid and protein constituents of rafts and caveolae in multidrug resistant cancer cells and their functional consequences. Glycoconj. J. 17 253-259 (2000). 

C. P. Yang, F. Galbiati, D. Volonte, S. B. Horwitz, and M. P. Lisanti. Upregulation of caveolin-1 and caveolae organelles in Taxol-resistant A549 cells. FEBS Lett. 439 368-372 (1998). 

P-glycoprotein (multi-drug resistance-1 ATP-binding cassette subfamily B) Plasma membrane, caveolae, and coated vesicles Immunogold antibody labeling by EM. Astrocytes Yes (Schirmer et al. 2003 Ronaldson et al. 2004)... 

Demeule M, Jodoin J, Gingras D, Beliv-eau R. 2000. P-glycoprotein is localized in caveolae in resistant cells and in brain capillaries. FEES Lett. 466 219-24... 

Several mechanisms of endocytotic pathways exist. These include clathrin-mediated endocytosis, caveolae-mediated endocytosis, macropinocytosis, and non-clathrin receptor-mediated endocytosis (Table 4). All of these pathways can be exploited for drug trafficking into resistant cancer cells. For example, the... 

A typical feature of caveola-mediated endocytosis is the formation of non-coated invaginations composed of detergent-resistant membrane components rich in cholesterol and sphingolipids, known as lipid rafts [56]. The importance of the caveola-mediated mechanism in the PTD-mediated internalization was confirmed in an experiment where the cellular uptake of Tat peptide was affected by drugs that either disrupt lipid rafts or alter caveolar trafficking [57]. Moreover, Tat-PTD-fused protein showed colocalization with a marker of caveolar uptake, caveolin, further strengthening the importance of the mechanism in the PTD-mediated internalization [57]. 

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