Endocytosis of resveratrol via lipid rafts and activation of downstream signaling pathways in cancer cells.
Fiche publication
Date publication
juillet 2011
Journal
Cancer prevention research (Philadelphia, Pa.)
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DELMAS Dominique, Dr LIZARD Gérard, Dr HICHAMI Aziz, Dr LIMAGNE Emeric
Tous les auteurs :
Colin D, Limagne E, Jeanningros S, Jacquel A, Lizard G, Athias A, Gambert P, Hichami A, Latruffe N, Solary E, Delmas D
Lien Pubmed
Résumé
trans-Resveratrol has been proposed to prevent tumor growth and to sensitize cancer cells to anticancer agents. Polyphenol entry into the cells has remained poorly understood. Here, we show that [(3)H]-resveratrol enters colon cancer cells (SW480, SW620, HT29) and leukemia U937 cells through a monensin (5-20 μmol/L) -sensitive process that suggests clathrin-independent endocytosis. Uptake of the molecule can be prevented by methyl-β-cyclodextrin (2-12 mg/mL), nystatin (12 ng/mL), and filipin (1 μg/mL), which all disrupt plasma membrane lipid rafts. Accordingly, radiolabeled resveratrol accumulates in sphingomyelin- and cholesterol-enriched cell fractions. Interestingly, extracellular signal-regulated kinases (ERK), c-Jun NH(2)-terminal kinases (JNK), and Akt also accumulate in lipid rafts on resveratrol exposure (IC(50) at 48 h ≈ 30 μmol/L in SW480 and U937 cells). In these rafts also, resveratrol promotes the recruitment, by the integrin α(V)β(3) (revealed by coimmunoprecipitation with an anti-integrin α(V)β(3) antibody), of signaling molecules that include the FAK (focal adhesion kinase), Fyn, Grb2, Ras, and SOS proteins. Resveratrol-induced activation of downstream signaling pathways and caspase-dependent apoptosis is prevented by endocytosis inhibitors, lipid raft-disrupting molecules, and the integrin antagonist peptide arginine-glycine-aspartate (500 nmol/L). Altogether, these data show the role played by lipid rafts in resveratrol endocytosis and activation of downstream pathways leading to cell death.
Mots clés
Anti-Bacterial Agents, pharmacology, Antibodies, Monoclonal, pharmacology, Antineoplastic Agents, Phytogenic, pharmacology, Apoptosis, drug effects, Blotting, Western, Colonic Neoplasms, drug therapy, Endocytosis, physiology, Extracellular Signal-Regulated MAP Kinases, metabolism, Filipin, pharmacology, Flow Cytometry, Focal Adhesion Kinase 1, metabolism, GRB2 Adaptor Protein, metabolism, Humans, Immunoenzyme Techniques, Immunoprecipitation, Integrin alphaVbeta3, immunology, Membrane Microdomains, physiology, Nystatin, pharmacology, Proto-Oncogene Proteins c-akt, metabolism, Proto-Oncogene Proteins c-fyn, metabolism, Signal Transduction, drug effects, Son of Sevenless Proteins, metabolism, Stilbenes, pharmacology, Tumor Cells, Cultured, beta-Cyclodextrins, pharmacology, ras Proteins, metabolism
Référence
Cancer Prev Res (Phila). 2011 Jul;4(7):1095-106