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Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin

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Abstract

Gliomas are the most aggressive of all human malignancies. Survivin is overexpressed in gliomas, and overexpression of survivin is associated with the progression of gliomas and the poor prognosis of glioma patients. Arsenic trioxide (ATO) is used in patients with acute promyelocytic leukemia and is active in vitro in several solid tumor cell lines. In the present study, the human glioma cell line U118-MG was used to investigate the anti-cancer effect of ATO in vitro and in vivo. The molecular mechanisms of the relationship between cell death (autophagy and apoptosis) and survivin were analyzed. ATO reduced cell viability through an increase in mitotic cells in a concentration-dependent manner. The mechanisms of ATO-induced autophagy and apoptosis were mediated by the inhibition of PI3K/Akt and the activation of MAPK signaling pathways. The ATO treatment of U118-MG cells pre-treated with specific chemical inhibitors of PI3K/AKT and MAPK significantly changed the cytotoxicity and the expression of survivin, suggesting that survivin plays a pivotal role in ATO-induced cell death. When U118-MG cells were transfected with survivin shRNA, the results demonstrated a significant increase in apoptotic and autophagic cells. In in vivo studies, the ATO treatment of SCID mice showed a significant tumor growth delay time and the decreased expression of survivin in tumor tissue. An important result from the current study is the finding that survivin could suppress both autophagy and apoptosis in glioma cells. This study suggests that ATO treatment or survivin inhibition could be a novel therapeutic strategy in malignant gliomas.

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Acknowledgments

This study was supported by the National Science Council, Taiwan (NSC 98-2314-B-006-034-MY2).

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The authors report no conflict of interest related to this study.

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Authors and Affiliations

  1. Department of Environmental and Occupational Health, National Cheng Kung University Medical College, 138 Sheng-Li Road, Tainan, 704, Taiwan

    Hui-Wen Chiu & Ying-Jan Wang

  2. Sustainable Environment Research Centre, National Cheng Kung University, Tainan, Taiwan

    Ying-Jan Wang

  3. School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

    Yuan-Soon Ho

  4. Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan

    Yuan-Soon Ho

  5. Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan

    Yuan-Soon Ho

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  1. Hui-Wen Chiu
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Correspondence to Ying-Jan Wang.

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Chiu, HW., Ho, YS. & Wang, YJ. Arsenic trioxide induces autophagy and apoptosis in human glioma cells in vitro and in vivo through downregulation of survivin. J Mol Med 89, 927–941 (2011). https://doi.org/10.1007/s00109-011-0763-1

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  • DOI: https://doi.org/10.1007/s00109-011-0763-1

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