title: Resveratrol enhances palmitate-induced ER stress and apoptosis in cancer cells.
abstract: BACKGROUND
  Palmitate, a saturated fatty acid (FA), is known to induce toxicity and cell death in various types of cells. Resveratrol (RSV) is able to prevent pathogenesis and/or decelerate the progression of a variety of diseases. Several in vitro and in vivo studies have also shown a protective effect of RSV on fat accumulation induced by FAs. Additionally, endoplasmic reticulum (ER) stress has recently been linked to cellular adipogenic responses. To address the hypothesis that the RSV effect on excessive fat accumulation promoted by elevated saturated FAs could be partially mediated by a reduction of ER stress, we studied the RSV action on experimentally induced ER stress using palmitate in several cancer cell lines.
  
  
  RESULTS
  We show that, unexpectedly, RSV promotes an amplification of palmitate toxicity and cell death and that this mechanism is likely due to a perturbation of palmitate accumulation in the triglyceride form and to a less important membrane fluidity variation. Additionally, RSV decreases radical oxygen species (ROS) generation in palmitate-treated cells but leads to enhanced X-box binding protein-1 (XBP1) splicing and C/EBP homologous protein (CHOP) expression. These molecular effects are induced simultaneously to caspase-3 cleavage, suggesting that RSV promotes palmitate lipoapoptosis primarily through an ER stress-dependent mechanism. Moreover, the lipotoxicity reversion induced by eicosapentaenoic acid (EPA) or by a liver X receptor (LXR) agonist reinforces the hypothesis that RSV-mediated inhibition of palmitate channeling into triglyceride pools could be a key factor in the aggravation of palmitate-induced cytotoxicity.
  
  
  CONCLUSIONS
  Our results suggest that RSV exerts its cytotoxic role in cancer cells exposed to a saturated FA context primarily by triglyceride accumulation inhibition, probably leading to an intracellular palmitate accumulation that triggers a lipid-mediated cell death. Additionally, this cell death is promoted by ER stress through a CHOP-mediated apoptotic process and may represent a potential anticancer strategy.
authors.affiliation: Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Rovira i Virgili University, Tarragona, 43007, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rojas
authors.affiliation: Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Rovira i Virgili University, Tarragona, 43007, Spain; Reproductive Biology and Gynecological Oncology Group, Center for Nanohealth, Institute of Life, Swansea University, Swansea, SA28PP, United Kingdom.
authors.forename: Belén
authors.initials: B
authors.lastname: Pan-Castillo
authors.affiliation: Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Rovira i Virgili University, Tarragona, 43007, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Valls
authors.affiliation: Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Rovira i Virgili University, Tarragona, 43007, Spain; Centre Tecnològic de Nutrició i Salut (CTNS), TECNIO, CEICS, Reus, 43204, Spain.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pujadas
authors.affiliation: Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Rovira i Virgili University, Tarragona, 43007, Spain; Centre Tecnològic de Nutrició i Salut (CTNS), TECNIO, CEICS, Reus, 43204, Spain.
authors.forename: Santi
authors.initials: S
authors.lastname: Garcia-Vallve
authors.affiliation: Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Rovira i Virgili University, Tarragona, 43007, Spain; Centre Tecnològic de Nutrició i Salut (CTNS), TECNIO, CEICS, Reus, 43204, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Arola
authors.affiliation: Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Rovira i Virgili University, Tarragona, 43007, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Mulero
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D000077185:Resveratrol; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D010168:Palmitates; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D013267:Stilbenes; D014157:Transcription Factors; D014280:Triglycerides; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051742:Transcription Factor CHOP; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; D000077185:Resveratrol