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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.

Authors
Kim, EH; Yoon, MJ; Kim, SU; Kwon, TK; Sohn, S; Choi, KS
Citation
Cancer research, 68(1):266-275, 2008
Journal Title
Cancer research
ISSN
0008-54721538-7445
Abstract
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 (As(2)O(3)) induces rapid apoptosis. Whereas TRAIL-mediated proteolytic processing of procaspase-3 was partially blocked in glioma cells, treatment with As(2)O(3) efficiently recovered TRAIL-induced activation of caspases. We also found that As(2)O(3) treatment of glioma cells significantly up-regulated DR5, a death receptor of TRAIL. Furthermore, suppression of DR5 expression by small interfering RNA (siRNA) inhibited As(2)O(3)/TRAIL-induced apoptosis of U87MG glioma cells, suggesting that DR5 up-regulation is critical for As(2)O(3)-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 As(2)O(3)-induced DR5 up-regulation. The involvement of CHOP in this process was confirmed by siRNA-mediated CHOP suppression, which not only attenuated As(2)O(3)-induced DR5 up-regulation but also inhibited the As(2)O(3)-stimulated TRAIL-induced apoptosis. These results therefore suggest that the CHOP-mediated DR5 up-regulation, brought about by As(2)O(3), 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 As(2)O(3) and TRAIL, demonstrating the safety of this treatment. In addition, As(2)O(3)-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 As(2)O(3) plus TRAIL may provide an effective and selective therapeutic strategy.
MeSH terms
Antineoplastic Agents/pharmacology*Apoptosis/drug effectsArsenicals/pharmacology*Astrocytes/drug effectsAstrocytes/metabolismBrain Neoplasms/metabolism*Caspase 3/metabolismGlioma/metabolism*HumansMembrane Proteins/metabolismOxides/pharmacology*Poly(ADP-ribose) Polymerases/metabolismProto-Oncogene Proteins/metabolismRNA, Small Interfering/pharmacologyReceptors, TNF-Related Apoptosis-Inducing Ligand/antagonists & inhibitorsReceptors, TNF-Related Apoptosis-Inducing Ligand/geneticsReceptors, TNF-Related Apoptosis-Inducing Ligand/metabolism*TNF-Related Apoptosis-Inducing Ligand/pharmacologyTranscription Factor CHOP/metabolism*Tumor Cells, CulturedUp-Regulation
DOI
10.1158/0008-5472.CAN-07-2444
PMID
18172319
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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