title: Resveratrol differentially regulates NAMPT and SIRT1 in Hepatocarcinoma cells and primary human hepatocytes.
abstract: Resveratrol is reported to possess chemotherapeutic properties in several cancers. In this study, we wanted to investigate the molecular mechanisms of resveratrol-induced cell cycle arrest and apoptosis as well as the impact of resveratrol on NAMPT and SIRT1 protein function and asked whether there are differences in hepatocarcinoma cells (HepG2, Hep3B cells) and non-cancerous primary human hepatocytes. We found a lower basal NAMPT mRNA and protein expression in hepatocarcinoma cells compared to primary hepatocytes. In contrast, SIRT1 was significantly higher expressed in hepatocarcinoma cells than in primary hepatocytes. Resveratrol induced cell cycle arrest in the S- and G2/M- phase and apoptosis was mediated by activation of p53 and caspase-3 in HepG2 cells. In contrast to primary hepatocytes, resveratrol treated HepG2 cells showed a reduction of NAMPT enzymatic activity and increased p53 acetylation (K382). Resveratrol induced NAMPT release from HepG2 cells which was associated with increased NAMPT mRNA expression. This effect was absent in primary hepatocytes where resveratrol was shown to function as NAMPT and SIRT1 activator. SIRT1 inhibition by EX527 resembled resveratrol effects on HepG2 cells. Furthermore, a SIRT1 overexpression significantly decreased both p53 hyperacetylation and resveratrol-induced NAMPT release as well as S-phase arrest in HepG2 cells. We could show that NAMPT and SIRT1 are differentially regulated by resveratrol in hepatocarcinoma cells and primary hepatocytes and that resveratrol did not act as a SIRT1 activator in hepatocarcinoma cells.
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schuster
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Penke
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Gorski
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Petzold-Quinque
authors.affiliation: Department of General-, Visceral- and Transplantation Surgery, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Damm
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Gebhardt
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.affiliation: Center for Pediatric Research Leipzig, University Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Garten
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D000077185:Resveratrol; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D012333:RNA, Messenger; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol