Valproic acid inhibits glioblastoma multiforme cell growth via paraoxonase 2 expression

Jen Ho Tseng, Cheng Yi Chen, Pei Chun Chen, Sheng Huang Hsiao, Chi Chen Fan, Yu Chih Liang, Chie Pein Chen

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

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 BclxL 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.

Original languageEnglish
Pages (from-to)14666-14679
Number of pages14
JournalOncotarget
Volume8
Issue number9
DOIs
Publication statusPublished - 2017

Keywords

  • Cell growth
  • Glioblastoma multiforme
  • Histone deacetylase
  • Paraoxonase 2
  • Valproic acid

ASJC Scopus subject areas

  • Oncology

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