Cancer Letters

Cancer Letters

Volume 185, Issue 2, 28 November 2002, Pages 153-161
Cancer Letters

Inhibition of migration of human glioblastoma cells by cerivastatin in association with focal adhesion kinase (FAK)

https://doi.org/10.1016/S0304-3835(02)00278-1Get rights and content

Abstract

To investigate the biological effect of cerivastatin on glioblastoma cells, we exposed them to various concentrations of cerivastatin. Cerivastatin exhibited dual effects on glioblastoma cells in a dose-dependent manner. Immunofluorescence microscopy showed disruption of actin stress fibers and focal adhesion plaques even at nanomolar concentrations. Matrigel assay demonstrated marked inhibition of glioblastoma cell invasion. Immunoblot analysis using a phosphospecific antibody against focal adhesion kinase (FAK) showed that inhibition of migration was associated with the down-regulation of tyrosine phosphorylation of FAK. Our data suggest that cerivastatin may be beneficial for combination therapy with conventional anti-cancer drugs by inhibiting the invasion of glioblastoma.

Introduction

Glioblastoma is the most common and most malignant tumor of the human central nervous system; the mean total length of survival is less than 1 year. Despite extensive clinical trials including surgical removal, radiotherapy, chemotherapy and immunotherapy, a good clinical outcome has remained an elusive goal. The success of all these treatments is hampered by such factors as the rapid growth, remarkable heterogeneity, high degree of infiltration, and extreme resistance to chemotherapy of glioblastoma cells. They possess a high ability to invade the surrounding brain tissue, a factor that contributes substantially to the inability to achieve curative total surgical resection. Therefore, to improve the prognosis of patients with glioblastoma, it is essential not only to overcome the chemoresistance of these tumor cells, but also to manage their invasiveness.

Statins, a family of 3-hydroxyl-3-methyl coenzyme A (HMG-CoA) reductase inhibitors commonly prescribed to lower cholesterol [1] which prevent the development of atherosclerosis [2], have been suggested to possess many other biological characteristics. These are anti-inflammatory [3], anti-oxidant [4], angiogenic, and anti-cancer [5], [6] effects. Cerivastatin is a novel statin that expresses a more powerful pharmacological action than do conventional statins [7]. It is hydrophobic in nature and has been shown to cross the blood–brain barrier even at nanomolar concentrations [8]. Therefore, it provides a great advantage over conventional statins for targeting tumor cells with a propensity for invading the surrounding brain.

In the present study, we used three malignant glioblastoma cell lines, U-251 MG, U-87 MG, and U-105 MG, to investigate the biological effects of cerivastatin against glioblastoma cells. We found that within the usual therapeutic serum concentration used to treat hypercholesterolemia, cerivastatin inhibited the adhesion and invasion of these cells without inducing cytotoxicity and that these effects were associated with the down-regulation of focal adhesion kinase (FAK) phosphorylation. Based on our results, we suggest that it may be possible to administer cerivastatin in combination with conventional anti-cancer drugs to decrease the invasiveness of glioblastoma cells without adding cytotoxic effects against normal cells.

Section snippets

Reagents

All standard culture reagents were obtained from Gibco BRL (Grand Island, NY). Cerivastatin was a gift from Bayer Yakuhin Co. (Tokyo, Japan). ADP-Ribosyltransferase C3 (Clostridium botulinum C3 transferase) was from Wako Pure Chemicals (Osaka, Japan). Geranylgeranylpyrophosphate (GGPP) and dl-Mevalonic Acid Lactone (l-mevalonate) were purchased from Sigma (St. Louis, MO). Antibodies to FAK and paxillin were purchased from Transduction Laboratories (Lexington, KY). Anti-FAK-Py397-phosphospecific

Results

To determine the biological effects of cerivastatin, we first investigated the morphological changes induced by 24 h exposure to varying concentrations of cerivastatin (10–100 nM). As shown in Fig. 1, cerivastatin led to drastic morphological changes in U-251 MG cells at a nanomolar concentration. Mild morphological changes were apparent at 50 nM concentrations (Fig. 1B). U-251 MG cells, which normally grow in flat epithelial-like shapes, became bipolar with prominent cell processes. Remarkable

Discussion

We demonstrated that cerivastatin, even at nanomolar concentrations, led to a disruption of the cytoskeleton, inhibiting the migration of glioblastoma cells. We also showed that this process was associated with the inactivation of FAK.

The biological effects of HMG-CoA reductase inhibitors on cell migration have been documented in a variety of cell systems, and previous reports concluded that the inhibition was due to cell toxicity observed at relatively high (micromolar) concentrations.

Acknowledgements

We would like to thank Nobue Uto, Yasuko Soejima, and Mihoko Nakajima for excellent technical assistance. We also thank Krishna Pada Sarker and Koichi Kawahara for helpful discussions.

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