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Arsenic Trioxide Sensitizes Human Glioma Cells, but not Normal Astrocytes, to TRAIL-Induced Apoptosis via CCAAT/Enhancer-Binding Protein Homologous Protein–Dependent DR5 Up-regulation

¹ Department of Molecular Science and Technology, Institute for Medical Sciences, ² Brain Disease Research Center, and ³ Laboratory of Cell Biology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea and ⁴ Department of Immunology, Keimyung University School of Medicine, Taegu, Korea

Requests for reprints: Kyeong Sook Choi, Department of Molecular Science and Technology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea. Phone: 82-31-219-4552; Fax: 82-31-219-4401; E-mail: kschoi{at}ajou.ac.kr.

The current study shows that treatment of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–resistant glioma cells with a combination of TRAIL and subtoxic doses of arsenic trioxide (As₂O₃) induces rapid apoptosis. Whereas TRAIL-mediated proteolytic processing of procaspase-3 was partially blocked in glioma cells, treatment with As₂O₃ efficiently recovered TRAIL-induced activation of caspases. We also found that As₂O₃ treatment of glioma cells significantly up-regulated DR5, a death receptor of TRAIL. Furthermore, suppression of DR5 expression by small interfering RNA (siRNA) inhibited As₂O₃/TRAIL-induced apoptosis of U87MG glioma cells, suggesting that DR5 up-regulation is critical for As₂O₃-induced sensitization of glioma cells to TRAIL-mediated apoptosis. Our results also indicate that an increase in CCAAT/enhancer binding protein homologous protein (CHOP) protein levels precedes As₂O₃-induced DR5 up-regulation. The involvement of CHOP in this process was confirmed by siRNA-mediated CHOP suppression, which not only attenuated As₂O₃-induced DR5 up-regulation but also inhibited the As₂O₃-stimulated TRAIL-induced apoptosis. These results therefore suggest that the CHOP-mediated DR5 up-regulation, brought about by As₂O₃, stimulates the TRAIL-mediated signaling pathway. This in turn leads to complete proteolytic processing of caspase-3, which is partially primed by TRAIL in glioma cells. In contrast to human glioma cells, astrocytes were very resistant to the combined administration of As₂O₃ and TRAIL, demonstrating the safety of this treatment. In addition, As₂O₃-mediated up-regulation of CHOP and DR5, as well as partial proteolytic processing of procaspase-3 by TRAIL, was not induced in astrocytes. Taken together, the present results suggest that the combined treatment of glioma cells with As₂O₃ plus TRAIL may provide an effective and selective therapeutic strategy. [Cancer Res 2008;68(1):266–75]

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