title: Resveratrol triggers the pro-apoptotic endoplasmic reticulum stress response and represses pro-survival XBP1 signaling in human multiple myeloma cells.
abstract: OBJECTIVE
  Resveratrol, trans-3, 4', 5,-trihydroxystilbene, suppresses multiple myeloma (MM). The endoplasmic reticulum (ER) stress response component inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) axis is essential for MM pathogenesis. We investigated the molecular action of resveratrol on IRE1α/XBP1 axis in human MM cells.
  
  
  METHODS
  Human MM cell lines ANBL-6, OPM2, and MM.1S were utilized to determine the molecular signaling events following treatment with resveratrol. The stimulation of IRE1α/XBP1 axis was analyzed by Western blot and reverse transcription polymerase chain reaction. The effect of resveratrol on the transcriptional activity of spliced XBP1 was assessed by luciferase assays. Chromatin immunoprecipitation was performed to determine the effects of resveratrol on the DNA binding activity of XBP1 in MM cells.
  
  
  RESULTS
  Resveratrol activated IRE1α as evidenced by XBP1 messenger RNA splicing and phosphorylation of both IRE1α and its downstream kinase c-Jun N-terminal kinase in MM cells. These responses were associated with resveratrol-induced cytotoxicity of MM cells. Resveratrol selectively suppressed the transcriptional activity of XBP1s while it stimulated gene expression of the molecules that are regulated by the non-IRE1/XBP1 axis of the ER stress response. Luciferase assays indicated that resveratrol suppressed the transcriptional activity of XBP1s through sirtuin 1, a downstream molecular target of resveratrol. Chromatin immunoprecipitation studies revealed that resveratrol decreased the DNA binding capacity of XBP1 and increased the enrichment of sirtuin 1 at the XBP1 binding region in the XBP1 promoter.
  
  
  CONCLUSIONS
  Resveratrol exerts its chemotherapeutic effect on human MM cells through mechanisms involving the impairment of the pro-survival XBP1 signaling and the activation of pro-apoptotic ER stress response.
authors: Department of Medicine/Hematology-Oncology and the Center for Bone Biology of UPMC, School of Medicine, University of Pittsburgh, Pa., USA.
authors: Feng-Ming
authors: FM
authors: Wang
authors: Deborah L
authors: DL
authors: Galson
authors: G David
authors: GD
authors: Roodman
authors: Hongjiao
authors: H
authors: Ouyang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D004722:Endoribonucleases / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D012326:RNA Splicing / Q000187:drug effects; D000071701:Regulatory Factor X Transcription Factors; D000077185:Resveratrol; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*; D000071717:X-Box Binding Protein 1
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D000071701:Regulatory Factor X Transcription Factors; D013267:Stilbenes; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol