title: Resveratrol sensitizes HepG2 cells to TRAIL-induced apoptosis.
abstract: Resveratrol is a natural polyphenol found in a wide variety of plants, including grapes, berries, and peanuts. Resveratrol can modulate a wide spectrum of molecular targets, including those involved in cancer signaling pathways. Here, we evaluated the role of resveratrol in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and examined the molecular mechanisms in the human hepatocellular carcinoma cell line HepG2. We used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay to assess cell viability, flow cytometry to analyze cell cycle and apoptosis, and immunoblotting to detect protein expression. Resveratrol decreased cell viability at a concentration of 100 μmol/l or higher. At a concentration of 50 μmol/l, resveratrol induced S phase arrest of the cell cycle without apoptosis. In addition, phospho-AMPK increased significantly in a dose-dependent manner. Resveratrol was found to synergistically augment TRAIL-induced apoptosis. The rates of early apoptosis were 3.4, 9.6, and 49.6% on treatment with 50 μmol/l resveratrol, 10 ng/ml TRAIL, and both reagents, respectively. Resveratrol significantly downregulated the expression of survivin in a dose-dependent manner. In conclusion, we found that that resveratrol could augment TRAIL sensitivity by downregulating survivin. These results suggest that combination resveratrol with TRAIL may be an effective new strategy for the treatment of hepatocellular carcinoma.
authors.affiliation: aFirst Department of Internal Medicine Departments of bMolecular and Laboratory Medicine cGastroenterology and Hepatology, Mie University School of Medicine, Tsu, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tameda
authors.forename: Kazushi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Katsuya
authors.initials: K
authors.lastname: Shiraki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Suguru
authors.initials: S
authors.lastname: Ogura
authors.forename: Chika
authors.initials: C
authors.lastname: Kasai
authors.forename: Misao
authors.initials: M
authors.lastname: Yoneda
authors.forename: Ryuji
authors.initials: R
authors.lastname: Okamoto
authors.forename: Norihiko
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takei
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nobori
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D056945:Hep G2 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D010766:Phosphorylation; D000077185:Resveratrol; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D013267:Stilbenes; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol