Flavonoids are polyphenolic compounds able to favour cholesterol-lipid-raft formation and control cell signaling pathways by targeting receptors at the cell surface. Procyanidins (Pcy) are oligomeric and polymeric flavonoids formed by catechins and epicatechins monomers trigger apoptosis by activating TRAIL-death receptors in human colon adenocarcinoma SW480 cells. Here, we investigated whether the apoptotic process triggered by apple procyanidins involving the up-regulation of TRAIL-death receptors DR4/DR5 at the cell surface was dependent on cell membrane lipid-raft formation. We report that Pcy-induced apoptosis was enhanced in presence of nystatin, a cholesterol-sequestering compound inhibiting lipid-raft formation, without changing DR4/DR5 receptor expression. Treatment of SW480 cells with TRAIL caused a 3.5-fold increased level of caveolin together with a 2- to 2.5-fold increased amount of DR4/DR5 proteins in lipid rafts. Pcy-treatment did not induce any alteration in the expression of DR4/DR5 proteins as well as of caveolin present in lipid-raft fractions. Pcy induced an activation of TRAIL-death receptor-mediated apoptosis by a mechanism independent of lipid-raft formation. These results highlight the potential of Pcy as a direct activator of TRAIL-death receptors in cell membrane even in the absence of lipid rafts. (C) 2009 Elsevier Inc. All rights reserved.