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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cytokines / genetics*
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Cytokines / metabolism
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G2 Phase Cell Cycle Checkpoints / drug effects
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Gene Expression Regulation, Neoplastic / drug effects*
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Nicotinamide Phosphoribosyltransferase / genetics*
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Nicotinamide Phosphoribosyltransferase / metabolism
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Organ Specificity
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Primary Cell Culture
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RNA, Messenger / genetics*
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RNA, Messenger / metabolism
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Resveratrol
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S Phase Cell Cycle Checkpoints / drug effects
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Signal Transduction
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Sirtuin 1 / genetics*
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Sirtuin 1 / metabolism
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Stilbenes / pharmacology*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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Cytokines
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RNA, Messenger
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Stilbenes
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Tumor Suppressor Protein p53
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Nicotinamide Phosphoribosyltransferase
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nicotinamide phosphoribosyltransferase, human
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SIRT1 protein, human
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Sirtuin 1
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Resveratrol
Grants and funding
The work was supported by German Research Foundation (DFG) KFO 152 “Atherobesity”? (to WK), DDG (Deutsche Diabetes Gesellschaft) (to SS and AG) and by LIFE ( Leipzig Research Center for Civilization Diseases, University of Leipzig ) (to WK and SS). LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative. The “virtual liver”? program is funded by the German Federal Ministry of Education and Research. We also acknowledge support from the German Research Foundation (DFG) and Leipzig University within the program of Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.