Quercetin enhances TRAIL-mediated apoptosis in colon cancer cells by inducing the accumulation of death receptors in lipid rafts

• Published in: Molecular cancer therapeutics Vol. 6; no. 9; pp. 2591 - 2599
• Main Authors: Psahoulia, Faiy H, Drosopoulos, Konstantinos G, Doubravska, Lenka, Andera, Ladislav, Pintzas, Alexander
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.09.2007
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; apoptosis; Apoptosis - drug effects; BH3 Interacting Domain Death Agonist Protein - metabolism; Caspases - drug effects; Caspases - metabolism; colon; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Cytochromes c - metabolism; Cytosol - drug effects; Cytosol - metabolism; Death Domain Receptor Signaling Adaptor Proteins - metabolism; Flow Cytometry; Fluorescent Antibody Technique; Humans; Immunoblotting; Immunoprecipitation; lipid rafts; Membrane Microdomains - drug effects; Membrane Microdomains - metabolism; Mitochondria - drug effects; Mitochondria - metabolism; quercetin; Quercetin - pharmacology; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Receptors, Tumor Necrosis Factor - metabolism; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TRAIL; Tumor Cells, Cultured - drug effects
• DOI: 10.1158/1535-7163.MCT-07-0001
• ISSN: 1535-7163

Cytokines such as tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) can induce apoptosis in colon cancer cells through engagement of death receptors. Nevertheless, evading apoptosis induced by anticancer drugs characterizes many types of cancers. This results in the need for combination therapy. In this study, we have investigated whether the flavonoid quercetin could sensitize human colon adenocarcinoma cell lines to TRAIL-induced apoptosis. We report that quercetin enhanced TRAIL-induced apoptosis by causing the redistribution of DR4 and DR5 into lipid rafts. Nystatin, a cholesterol-sequestering agent, prevented quercetin-induced clustering of death receptors and sensitization to TRAIL-induced apoptosis in colon adenocarcinoma cells. In addition, our experiments show that quercetin, in combination with TRAIL, triggered the mitochondrial-dependent death pathway, as shown by Bid cleavage and the release of cytochrome c to the cytosol. Together, our findings propose that quercetin, through its ability to redistribute death receptors at the cell surface, facilitates death-inducing signaling complex formation and activation of caspases in response to death receptor stimulation. Based on these results, this study provides a challenging approach to enhance the efficiency of TRAIL-based therapies. [Mol Cancer Ther 2007;6(9):2591–9]