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Nuclear Translocation of β-catenin is Essential for Glioma Cell Survival

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Abstract

Identification of molecular pathways that are essential for cancer cell survival is vital for understanding the underlying biology, as well as to design effective cancer therapeutics. β-catenin, a multifunctional oncogenic protein, participates in cell development. Its multifaceted functions primarily lie to the subcellular distribution. The present study demonstrated that β-catenin accumulated in the nucleus to a greater extent in high-grade gliomas compared with low-grade gliomas. In addition, nuclear localization correlated with a worse prognosis for patients, as determined by immunohistochemical analysis of 74 glioma samples. Nuclear expression of β-catenin was down-regulated in LN229 and U87 glioma cells by a small molecule inhibitor of β-catenin/TCF4 signaling, demonstrating strongly inhibited β-catenin/TCF4 transcriptional activity and STAT3 luciferase activity, as well as decreased mRNA and protein levels of nuclear β-catenin, TCF4, EGFR, AKT1, AKT2 and STAT3. Furthermore, repressed nuclear translocation of β-catenin resulted in inhibition of proliferation and invasiveness, and also induced apoptosis of glioma cells. Similar results were also observed in vivo; intratumoral injection of such small molecule inhibitor downregulated expression of nuclear β-catenin, TCF4, and components of the EGFR pathway, and also delayed tumor growth in nude mice harboring subcutaneous U87 xenografts. Results from the present study provided evidence that nuclear accumulation of β-catenin participated in malignant progression of gliomas and implicated poor prognosis, highlighting it as a potential therapeutic target for gliomas.

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Acknowledgments

This work was supported by China National Natural Scientific Fund (30971136, 81001128, 81172406), Tianjin Science and Technology Committee (09JCZDJC17600, 10SYSYJC28800), National High Technology Research and Development Program 863(2012AA02A508). The authors report no conflict of interest concerning materials or methods used in this study, or findings specified in this paper.

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Authors and Affiliations

  1. Department of Neurosurgery, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Medical University General Hospital, 152, Anshan Road, Heping, Tianjin, 300052, People’s Republic of China

    Zhendong Shi, Xiaomin Qian, Junxia Zhang, Shanjun Zhu, Jialin Zhu, Luyue Chen, Kailiang Zhang, Lei Han, Peiyu Pu & Chunsheng Kang

  2. Tianjin Medical University Basic Medical College, Tianjin, 300070, People’s Republic of China

    Lanquan Li

  3. Department of Neurology, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China

    Shizhu Yu

  4. Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China

    Tao Jiang

Authors
  1. Zhendong Shi
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  2. Xiaomin Qian
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  3. Lanquan Li
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  4. Junxia Zhang
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  5. Shanjun Zhu
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  6. Jialin Zhu
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  7. Luyue Chen
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  8. Kailiang Zhang
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  9. Lei Han
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  10. Shizhu Yu
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  11. Peiyu Pu
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  12. Tao Jiang
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  13. Chunsheng Kang
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Corresponding author

Correspondence to Chunsheng Kang.

Additional information

Zhendong Shi, Xiaomin Qian and Lanquan Li contributed equally to this work

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Shi, Z., Qian, X., Li, L. et al. Nuclear Translocation of β-catenin is Essential for Glioma Cell Survival. J Neuroimmune Pharmacol 7, 892–903 (2012). https://doi.org/10.1007/s11481-012-9354-3

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  • DOI: https://doi.org/10.1007/s11481-012-9354-3

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