Resveratrol via sirtuin-1 downregulates RE1-silencing transcription factor (REST) expression preventing PCB-95-induced neuronal cell death

• Published in: Toxicology and applied pharmacology 2015-11, Vol.288 (3), p.387-398
• Main Authors: Guida, Natascia, Laudati, Giusy, Anzilotti, Serenella, Secondo, Agnese, Montuori, Paolo, Di Renzo, Gianfranco, Canzoniero, Lorella M.T., Formisano, Luigi
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; APOPTOSIS; c-Jun; CARBAZOLES; Carbazoles - pharmacology; Cell Death - drug effects; Cell Line, Tumor; Chromatin Immunoprecipitation; DIOXIN; Down-Regulation; Gene Silencing; HISTONES; Humans; LACTATE DEHYDROGENASE; LACTATES; MESSENGER-RNA; NERVE CELLS; NERVOUS SYSTEM DISEASES; Neurons - cytology; Neurons - drug effects; PCB-95; POLYCHLORINATED BIPHENYLS; Polychlorinated Biphenyls - toxicity; POLYPHENOLS; Promoter Regions, Genetic; RATS; Reactive Oxygen Species - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; REST; Resveratrol; Signal Transduction; SIRT1; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; STILBENE; Stilbenes - pharmacology; TIME DEPENDENCE; TRANSCRIPTION; TRANSCRIPTION FACTORS
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.08.010

Resveratrol (3,5,4′-trihydroxystilbene) (RSV), a polyphenol widely present in plants, exerts a neuroprotective function in several neurological conditions; it is an activator of class III histone deacetylase sirtuin1 (SIRT1), a crucial regulator in the pathophysiology of neurodegenerative diseases. By contrast, the RE1-silencing transcription factor (REST) is involved in the neurotoxic effects following exposure to polychlorinated biphenyl (PCB) mixture A1254. The present study investigated the effects of RSV-induced activation of SIRT1 on REST expression in SH-SY5Y cells. Further, we investigated the possible relationship between the non-dioxin-like (NDL) PCB-95 and REST through SIRT1 to regulate neuronal death in rat cortical neurons. Our results revealed that RSV significantly decreased REST gene and protein levels in a dose- and time-dependent manner. Interestingly, overexpression of SIRT1 reduced REST expression, whereas EX-527, an inhibitor of SIRT1, increased REST expression and blocked RSV-induced REST downregulation. These results suggest that RSV downregulates REST through SIRT1. In addition, RSV enhanced activator protein 1 (AP-1) transcription factor c-Jun expression and its binding to the REST promoter gene. Indeed, c-Jun knockdown reverted RSV-induced REST downregulation. Intriguingly, in SH-SY5Y cells and rat cortical neurons the NDL PCB-95 induced necrotic cell death in a concentration-dependent manner by increasing REST mRNA and protein expression. In addition, SIRT1 knockdown blocked RSV-induced neuroprotection in rat cortical neurons treated with PCB-95. Collectively, these results indicate that RSV via SIRT1 activates c-Jun, thereby reducing REST expression in SH-SY5Y cells under physiological conditions and blocks PCB-95-induced neuronal cell death by activating the same SIRT1/c-Jun/REST pathway. •Resveratrol via SIRT1/c-Jun downregulates REST mRNA and protein in SH-SY5Y cells.•Non-dioxin-like (NDL) PCB-95 is cytotoxic to SH-SY5Y cells and cortical neurons.•PCB-95-induced cytotoxicity is mediated by REST.•PCB-95-induced cell death is inhibited by resveratrol.