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Research Articles: Therapeutics, Targets, and Development

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

¹ Laboratory of Signal Mediated Gene Expression, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece; ² Laboratory of Cell Signaling and Apoptosis, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic; and ³ Department of Medicine, School of Health Sciences, University of Thessaly, Larisa, Greece

Requests for reprints: Alexander Pintzas, Laboratory of Signal Mediated Gene Expression, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, 48 Vasileos Konstantinou Avenue, Athens 11635, Greece. Phone: 30-210-7273753; Fax: 30-210-7273745. E-mail: apint{at}eie.gr

Abstract

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]

Grant support: Greek General Secretariat for Research and Technology Research Programs PENED 01ED227 and 01ED113 (A. Pintzas) and Ministry of Education (1M6837805001) and institutional (AV0Z50520514) Czech grants (L. Andera).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/ 2/07; revised 6/26/07; accepted 8/ 1/07.