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  • Original Paper
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Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3

Abstract

Arsenic trioxide (As2O3) has shown considerable efficacy in treating hematological malignancies with induction of programmed cell death (PCD) type I, apoptosis. However, the mechanisms underlying the antitumor effect of As2O3 on solid tumors are poorly defined. Previously, we reported that As2O3 induced autophagic cell death (PCD type II) but not apoptosis in human malignant glioma cell lines. The purpose of this study was to elucidate the molecular pathway leading to autophagic cell death. In this study, we demonstrated that the cell death was accompanied by involvement of autophagy-specific marker, microtubule-associated protein light chain 3 (LC3), and damage of mitochondrial membrane integrity, but not by caspase activation. Analysis by cDNA microarray, RT–PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) and its homologue BNIP3-like (BNIP3L), were upregulated in As2O3-induced autophagic cell death. Exogenous expression of BNIP3, but not BNIP3L, induced autophagic cell death in malignant glioma cells without As2O3 treatment. When upregulation of BNIP3 induced by As2O3 was suppressed by a dominant-negative effect of the transmembrane-deleted BNIP3 (BNIP3ΔTM), autophagic cell death was inhibited. In contrast, BNIP3 transfection augmented As2O3-induced autophagic cell death. These results suggest that BNIP3 plays a central role in As2O3-induced autophagic cell death in malignant glioma cells. This study adds a new concept to characterize the pathways by which As2O3 acts to induce autophagic cell death in malignant glioma cells.

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Acknowledgements

We thank Dr A Yamamoto and Dr N Mizushima for a critical review. We also thank Dr S Waxman, Dr AH Greenberg, Dr D Dubik, Dr N Mizushima, and Dr T Yoshimori for gifts of reagents. This study was supported in part by the USPHS Grants CA88936 and CA106310, a start-up fund from The University of Texas MD Anderson Cancer Center, a generous donation from the Anthony D Bullock III Foundation, and the Cancer Center Support Grant (CCSG)/Shared Resources.

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Correspondence to Seiji Kondo.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Kanzawa, T., Zhang, L., Xiao, L. et al. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene 24, 980–991 (2005). https://doi.org/10.1038/sj.onc.1208095

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