Valproic acid affected the survival and invasiveness of human glioma cells through diverse mechanisms

Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei, Taiwan.
Journal of Neuro-Oncology (Impact Factor: 3.07). 04/2012; 109(1):23-33. DOI: 10.1007/s11060-012-0871-y
Source: PubMed


The effects of valproic acid (VPA) on the viability, apoptosis, and invasiveness of two glioma cells (A172 and T98G) and the underlying mechanisms were studied. VPA induced cytotoxicity and apoptosis, and suppressed the invasiveness of both cells. VPA increased the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 in A172 cells, but decreased it in T98G cells. siRNA blockade of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression partially reversed VPA-mediated effects in T98G cells, but had no effect on A172 cells. VPA increased the expression of phospho-JNK1 and phospho-ERK1/2 in A172 cells, but decreased it in T98G cells. Inhibition of JNK1 and/or ERK1/2 partially reversed the VPA effects in A172 cells. In conclusion, the effects of VPA (loss of viability, increased apoptosis, and decreased invasiveness) are, at least partly, mediated through the RECK-MMPs pathway in T98G cells and the mitogen-activated protein kinase pathways in A172 cells. The action of VPA seems to be cell type-specific in glioma cells.

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    ABSTRACT: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a tumor and metastasis suppressor gene, is critical for the regulation of the invasive and metastatic activities of tumor cells. RECK is down-regulated in some malignancies and its expression is positively correlated with survival of patients with cancer. Patients with malignant glioma have poor prognosis. Since RECK expression decreases as the tumor stage progresses from less invasive grade II glioma to invasive glioblastoma multiforme, up-regulation of RECK by natural or synthetic agents might be a valuable therapeutic option for glioma. Histone deacetylase inhibitors and non-steroidal anti-inflammatory drugs have been widely used clinically and demonstrated to increase RECK expression in cancer cells, thus they might be used as RECK inducers. In this article, the functions of RECK and the role of RECK in glioma are reviewed, with emphasis on the potential application of RECK inducers in the treatment of glioma.
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    ABSTRACT: Matrix metalloproteinase 9 (MMP-9) is one of the most studied enzymes in cancer. MMP-9 can cleave proteins of the extracellular matrix and a large number of receptors and growth factors. Accordingly, its expression must be tightly regulated to avoid excessive enzymatic activity, which is associated with disease progression. Although we know that epigenetic mechanisms play a central role in controlling mmp-9 gene expression, predicting how epigenetic drugs could be used to suppress mmp-9 gene expression is not trivial because epigenetic drugs also regulate the expression of key proteins that can tip the balance towards activation or suppression of MMP-9. Here, we review how our understanding of the biology and expression of MMP-9 could be exploited to augment clinical benefits, most notably in terms of the prevention and management of degenerative diseases and cancer.
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