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Acrolein sensitizes human renal cancer Caki cells to TRAIL-induced apoptosis via ROS-mediated up-regulation of death receptor-5 (DR5) and down-regulation of Bcl-2.

Authors
Yang, ES; Woo, SM; Choi, KS; Kwon, TK
Citation
Experimental cell research, 317(18):2592-2601, 2011
Journal Title
Experimental cell research
ISSN
0014-48271090-2422
Abstract
TRAIL resistance in many cancer cells is one of the major problems in TRAIL-based cancer therapy. Thus, the agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are strictly needed for the improvement of anti-cancer effect of TRAIL. Acrolein is a byproduct of lipid peroxidation, which has been involved in pulmonary, cardiac and neurodegenerative diseases. We investigated whether acrolein, an α,β-unsaturated aldehyde, can potentiate TRAIL-induced apoptosis in human renal cancer cells. The combined treatment with acrolein and TRAIL significantly induced apoptosis, and stimulated of caspase-3 activity, DNA fragmentation, and cleavage of PARP. We found that acrolein down-regulated the protein level of Bcl-2 and Bcl-2 overexpression inhibited the cell death induced by the combined treatment with acrolein and TRAIL. In addition, acrolein up-regulated C/EBP homologous protein (CHOP) and TRAIL death receptor 5 (DR5) and down-regulation of CHOP or DR5 expression using the respective small interfering RNA significantly attenuated the apoptosis induced by acrolein plus TRAIL. Interestingly, pretreatment with an antioxidant, N-acetylcysteine (NAC), inhibited not only CHOP and DR5 up-regulation but also the cell death induced by acrolein plus TRAIL. Taken together, our results demonstrated that acrolein enhances TRAIL-induced apoptosis in Caki cells through down-regulation of Bcl-2 and ROS dependent up-regulation of DR5.
MeSH terms
Acrolein/*pharmacologyApoptosis/*drug effectsDose-Response Relationship, DrugDown-Regulation/drug effectsGene Expression Regulation/*drug effectsHumansProto-Oncogene Proteins c-bcl-2/*metabolismReactive Oxygen Species/*metabolismReceptors, TNF-Related Apoptosis-Inducing Ligand/*metabolismRecombinant Proteins/metabolismStructure-Activity RelationshipTNF-Related Apoptosis-Inducing Ligand/*metabolismTumor Cells, CulturedUp-Regulation/drug effects
DOI
10.1016/j.yexcr.2011.08.005
PMID
21854768
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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