title: 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.
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.
authors.affiliation: Department of Molecular Science and Technology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Yoon
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Seonghyang
authors.initials: S
authors.lastname: Sohn
authors.forename: Kyeong Sook
authors.initials: KS
authors.lastname: Choi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C090121:BNIP3 protein, human; C497249:DDIT3 protein, human; D008565:Membrane Proteins; D010087:Oxides; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D000077237:Arsenic Trioxide