title: Valproic acid inhibits glioblastoma multiforme cell growth via paraoxonase 2 expression.
abstract: We studied the potential mechanisms of valproic acid (VPA) in the treatment of glioblastoma multiforme (GBM). Using the human U87, GBM8401, and DBTRG-05MG GBM-derived cell lines, VPA at concentrations of 5 to 20 mM induced G2/M cell cycle arrest and increased the production of reactive oxygen species (ROS). Stress-related molecules such as paraoxonase 2 (PON2), cyclin B1, cdc2, and Bcl-xL were downregulated, but p27, p21 and Bim were upregulated by VPA treatment. VPA response element on the PON2 promoter was localized at position -400/-1. PON2 protein expression was increased in GBM cells compared with normal brain tissue and there was a negative correlation between the expression of PON2 and Bim. These findings were confirmed by the public Bredel GBM microarray (Gene Expression Omnibus accession: GSE2223) and the Cancer Genome Atlas GBM microarray datasets. Overexpression of PON2 in GBM cells significantly decreased intracellular ROS levels, and PON2 expression was decreased after VPA stimulation compared with controls. Bim expression was significantly induced by VPA in GBM cells with PON2 silencing. These observations were further shown in the subcutaneous GBM8401 cell xenograft of BALB/c nude mice. Our results suggest that VPA reduces PON2 expression in GBM cells, which in turn increases ROS production and induces Bim production that inhibits cancer progression via the PON2-Bim cascade.
authors.affiliation: Department of Neurosurgery, Taipei City Hospital, Renai Branch, Taipei 106, Taiwan.|Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Jen-Ho
authors.initials: JH
authors.lastname: Tseng
authors.affiliation: Department of Medical Research, MacKay Memorial Hospital, New Taipei City 251, Taiwan.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Medical Research, MacKay Memorial Hospital, New Taipei City 251, Taiwan.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Taipei City Hospital, Renai Branch, Taipei 106, Taiwan.|College of Science, National Chengchi University, Taipei 116, Taiwan.
authors.forename: Sheng-Huang
authors.initials: SH
authors.lastname: Hsiao
authors.affiliation: Department of Physiology, MacKay Memorial Hospital, Taipei 104, Taiwan.
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Fan
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liang
authors.affiliation: Department of Medical Research, MacKay Memorial Hospital, New Taipei City 251, Taiwan.|Department of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Chie-Pein
authors.initials: CP
authors.lastname: Chen
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D018682:GABA Agents / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014635:Valproic Acid / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000072224:Bcl-2-Like Protein 11; D018682:GABA Agents; D017382:Reactive Oxygen Species; D014635:Valproic Acid; D043303:Aryldialkylphosphatase; C468411:PON2 protein, human
keywords: cell growth; glioblastoma multiforme; histone deacetylase; paraoxonase 2; valproic acid