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Expression of Nur77 induced by an n-butylidenephthalide derivative promotes apoptosis and inhibits cell growth in oral squamous cell carcinoma

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Summary

In spite of numerous advances, the 5-year survival rate for head and neck squamous cell cancer has remained largely stagnant and few new anti-tumor drugs have been developed. PCH4, a derivative of n-butylidenephthalide, has been investigated for its anti-tumor effects on oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anti-tumor mechanism of a potential target gene, Nur77, in OSCC cells, which can be induced by PCH4 treatment. Data show that PCH4 promoted Nur77 translocation from the nucleus to the cytoplasm and induced cell apoptosis in OSCC cells. When Nur77 translocation was blocked, the degree of tumor apoptosis caused by PCH4 was significantly inhibited (p < 0.05). Within the MAPK pathway, PCH4 only induced JNK phosphorylation. Furthermore, treatment with a JNK inhibitor significantly reduced PCH4-induced apoptosis (p < 0.05) and decreased PCH4-induced Nur77 expression (p < 0.05). In a xenograft animal model, administration of PCH4 also showed anti-tumor effects. We have demonstrated that OSCC cells are sensitive to PCH4 and that Nur77 protein translocation from the nucleus to the cytoplasm might be associated with the induction of apoptosis by PCH4. These results indicate that PCH4 may serve as a potential anti-tumor drug for OSCC therapy.

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Abbreviations

OSCC:

Oral squamous cell carcinoma

PCH4:

(Z)-N-(2-(dimethyl-amino) ethyl)-2-(3-((3-oxo-isobenzofuran- 1(3H)-ylidene) methyl) phenoxy) acetamide)

BP:

butylidenephthalide

RT-PCR:

reverse transcription-polymerase chain reaction

DMSO:

dimethyl sulfoxide

PCR:

polymerase chain reaction

siRNA:

small interfering RNA

MTT:

3-(4,5-dimethyl thizol-2-yl)-2,5-diphenyl tetrazolium bromide

PVDF:

polyvinyldenefluoride

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Acknowledgements

This work was supported by a Grant from National Science Council of the Republic of China (96-2320-B-039-044-MY3) and China Medical University Hospital of the Republic of China (DMR-99-073).

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan

    Po Yen Liu & Jim Jinn-Chyuan Sheu

  2. Department of Pathology, China Medical University, Taichung, 40402, Taiwan

    Po Cheng Lin

  3. Center for Neuropsychiatry, China Medical University and Hospital, Taichung, 40704, Taiwan

    Po Cheng Lin & Shinn Zong Lin

  4. Department of Chemistry, Tung Hai University, Taichung, 40704, Taiwan

    Cheng Tung Lin

  5. Graduate Institute of Basic Medical Science, China Medical University, Taichung, 40402, Taiwan

    Ya Jung Liu & Wan Chen Wu

  6. Department of Respiratory Care, Veterans General Hospital-Taipei, Taipei, 11217, Taiwan

    Li Ing Ho

  7. Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, No. 1, Sec. 2, Da Hsueh Road, Hualien, 97401, Taiwan

    Li Fu Chang, Syue Rong Chen & Tzyy Wen Chiou

  8. Department of Laboratory Medicine, Hualian Armed Forces General Hospital, Hualian, 97144, Taiwan

    Jay Chen

  9. Graduate Institute of Networking and Multimedia, National Taiwan University, Taipei, 10617, Taiwan

    Yeu Chern Harn

  10. Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, 65152, Taiwan

    Shinn Zong Lin

  11. Department of Pediatrics, China Medical University Hospital, Taichung, 40447, Taiwan

    Chang Hai Tsai

  12. Department of Healthcare Administration, Asia University, Taichung, 41354, Taiwan

    Chang Hai Tsai

  13. Department of Pathology, China Medical University and Hospital, No.2 Yuh-Der Road, Taichung, 40447, Taiwan

    Horng Jyh Harn

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  1. Po Yen Liu
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  2. Jim Jinn-Chyuan Sheu
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  3. Po Cheng Lin
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  7. Li Fu Chang
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  8. Wan Chen Wu
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  9. Syue Rong Chen
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  12. Shinn Zong Lin
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  13. Chang Hai Tsai
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  14. Tzyy Wen Chiou
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  15. Horng Jyh Harn
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Corresponding author

Correspondence to Horng Jyh Harn.

Additional information

The last two corresponding authors (Tzyy Wen Chiou and Horng Jyh Harn) contributed equally to this work.

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Liu, P.Y., Sheu, J.JC., Lin, P.C. et al. Expression of Nur77 induced by an n-butylidenephthalide derivative promotes apoptosis and inhibits cell growth in oral squamous cell carcinoma. Invest New Drugs 30, 79–89 (2012). https://doi.org/10.1007/s10637-010-9518-z

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  • DOI: https://doi.org/10.1007/s10637-010-9518-z

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