Overexpression of the orphan receptor Nur77 and its translocation induced by PCH4 may inhibit malignant glioma cell growth and induce cell apoptosis

Authors

  • Li-Fu Chang MS,

    1. Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, ROC
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  • Po-Cheng Lin PhD,

    1. Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, ROC
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  • Li-Ing Ho MD,

    1. Department of Respiratory Care, Veterans General Hospital-Taipei, Taipei, Taiwan, ROC
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  • Po-Yen Liu MS,

    1. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan, ROC
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  • Wan-Chen Wu MS,

    1. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, ROC
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  • I-Ping Chiang MD,

    1. Department of Pathology, China Medical University Hospital, Taichung, Taiwan, ROC
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  • Hui-Wen Chang MD,

    1. Department of Pathology, China Medical University Hospital, Taichung, Taiwan, ROC
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  • Shinn-Zong Lin MD,

    1. Center for Neuropsychiatry, China Medical University and Hospital, Taichung, 40447, Taiwan, ROC
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  • Yeu-Chern Harn BS,

    1. Graduate Institute of Networking and Multimedia, National Taiwan University, Taipei, Taiwan, ROC
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  • Horng-Jyh Harn MD,

    Corresponding author
    1. Department of Pathology, China Medical University Hospital, Taichung, Taiwan, ROC
    2. Department of Medicine, China Medical University, Taichung, Taiwan, ROC
    • Horng-Jyh Harn, Department of Pathology, China Medical University Hospital, 2 Yuh-Der Road, Taichung, Taiwan 40447, ROC. Fax: 886-4-22052121 ext 2566.===

      Tzyy-Wen Chiou, Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Rd., Shoufeng, Hualien, Taiwan, ROC. Fax: 886-3-8630262.===

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  • Tzyy-Wen Chiou PhD

    Corresponding author
    1. Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, ROC
    • Horng-Jyh Harn, Department of Pathology, China Medical University Hospital, 2 Yuh-Der Road, Taichung, Taiwan 40447, ROC. Fax: 886-4-22052121 ext 2566.===

      Tzyy-Wen Chiou, Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Rd., Shoufeng, Hualien, Taiwan, ROC. Fax: 886-3-8630262.===

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  • Li-Fu Chang and Po-Cheng Lin contributed equally to this work.

Abstract

Background

In previous study, n-butylidenephthalide (BP), a natural compound from Angelica sinensis, has anti-glioblastoma multiform (GBM) cell effects. In this study, we modified BP structure to increase anti-GBM cell effects. The anti-GBM cell effects of one derivative of BP, (Z)-N-(2-(dimethylamino)ethyl)-2-(3-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide (PCH4) were tested in vitro and in vivo.

Methods

MTT assay and PI/Annexin V assay were performed to evaluate the anti-GBM effects of PCH4. The Nur77 expression and translocation were assayed by RT-PCR and Western blot. The Nur77 siRNA was used to downregulate the Nur77 expression. The JNK inhibitor (SP600125) was used to block the JNK pathway.

Results

The anti-GBM effect of PCH4 is four times more than BP. The IC50 of PCH4 on DBTRG-05MG cells was 50 µg/ml. Nur77 expression and translocation from the nucleus to the cytoplasm were important in PCH4-induced apoptosis. Furthermore, the downregulation of PCH4-induced Nur77 expression by Nur77 siRNA reduced PCH4-induced apoptosis. In addition, PCH4-induced apoptosis was associated with the JNK pathway. The JNK inhibitor, SP600125, inhibited Nur77 mRNA expression and reduced PCH4-induced apoptosis.

Conclusions

In conclusion, PCH4, a derivative of BP, induced Nur77-mediated apoptosis via the JNK pathway and this mechanism, which is different from that of BP, may explain the increase in the anti-tumor effects on GBM. J. Surg. Oncol. 2011; 103:442–450. © 2011 Wiley-Liss, Inc.

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