Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3
Takao Kanzawa1,3, Li Zhang2, Lianchun Xiao2, Isabelle M Germano3, Yasuko Kondo1,3 and Seiji Kondo1,3
1Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
3Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY 10510, USA
Correspondence to: S Kondo, Department of Neurosurgery, Unit 64, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. E-mail: firstname.lastname@example.org
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 (BNIP3TM), 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.
Oncogene (2005) 24, 980-991. doi:10.1038/sj.onc.1208095
Published online 13 December 2004
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