Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Resveratrol and Health Importance of lipid microdomains, rafts, in absorption, delivery, and biological effects of resveratrol Dominique Delmas, 1,2 Virginie Aires, 1,2 Didier J. Colin, 3 Emeric Limagne, 1,2 Alessandra Scagliarini, 1,2 Alexia K. Cotte, 1,2 and Franc ¸ois Ghiringhelli 1,2 1 University of Burgundy, Dijon, France. 2 Chemotherapy, Lipid Metabolism and Antitumoral Immune Response Team, INSERM Research Center U866, Dijon, France. 3 Center for Biomedical Imaging (CIBM)–microPET Imaging Laboratory, University of Geneva, Geneva, Switzerland Address for correspondence: Dominique Delmas, Faculty of Medicine, INSERM Research Center UMR866 “Lipids, Nutrition, Cancers,” 7 Bd Jeanne d’Arc, 21000 Dijon, France. ddelmas@u-bourgogne.fr The preventive effects of the phytoalexin trans-resveratrol toward cancer have been largely described at the cellular and molecular levels in both in vivo and in vitro models; however, its primary targets are still poorly identified. In this review, we show the crucial role of cell membrane microdomains, that is, lipid rafts, not solely in the initiation of the early biochemical events triggered by resveratrol leading to cancer cell death, but also in resveratrol absorption and distribution. Resveratrol accumulates in lipid rafts and is then taken up by cells through raft- dependent endocytosis. These events allow early activation of kinase pathways and redistribution of cell death receptors within lipid microdomains, events ultimately leading to apoptotic cell death. Keywords: resveratrol; transport; cancer; rafts; apoptosis Introduction Resveratrol or 3,4 ′ ,5-trihydroxystilbene is a sec- ondary metabolite produced in limited plant species and found in many natural foods (e.g., grapes, red wine, purple grape juice, and some berries). 1 In plants, resveratrol is mostly found in the trans-resveratrol-3-O--d-glucoside form, which is often referred to as piceid. Like many other plant polyphenols (i.e., flavonoids, epicatechins), resver- atrol presents interesting properties against cancers. Resveratrol is able to delay or to prevent the stages of carcinogenesis. 2,3 These beneficial effects have been supported by observations at the cellular and molec- ular levels in both in vitro and in vivo models and reinforce the interest in grape products and dietary supplements for cancer therapy. In the field of chemoprevention, the ability of resveratrol to prevent the occurrence of various car- cinomas is related to the inhibition of the tumor cell cycle, 4,5 the activation of signaling pathways that involve kinase activations, and/or the induction of the proteolytic cascade of caspases to trigger tumor cell apoptosis. 6,7 Although the beneficial effects of resveratrol have largely been elucidated, very little is known about the mechanisms of resveratrol cellular uptake and how resveratrol initiates its biological ef- fects. Here we review the essential role played by par- ticular plasma membrane microdomains, also called rafts or lipid rafts, in both resveratrol absorption and distribution and in early resveratrol-induced signal- ing pathways leading to apoptotic cancer cell death. The last part of this review discusses the potential role of lipid rafts in resveratrol-mediated effects and in the potential restoration of tumor cell sensitivity to death receptor ligands. Lipid rafts as dynamic membrane structures The plasma membrane of mammalian cells is a bilayer primarily composed of thousands of types of lipids and proteins. 8 Besides delineating intra- and extracellular compartments, the plasma mem- brane constitutes a selective barrier through which information and matter pass. The plasma mem- brane structure was originally described by Singer and Nicholson in 1970 as a fluid mosaic in which doi: 10.1111/nyas.12177 90 Ann. N.Y. Acad. Sci. 1290 (2013) 90–97 C  2013 New York Academy of Sciences.