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
