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Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant hepatoma cells to TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of DR5.

Authors
Kim, H; Kim, EH; Eom, YW; Kim, WH; Kwon, TK; Lee, SJ; Choi, KS
Citation
Cancer research, 66(3):1740-1750, 2006
Journal Title
Cancer research
ISSN
0008-54721538-7445
Abstract
Sulforaphane is a chemopreventive agent present in various cruciferous vegetables, including broccoli. Here, we show that treatment with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in combination with subtoxic doses of sulforaphane significantly induces rapid apoptosis in TRAIL-resistant hepatoma cells. Neither TNF-alpha- nor Fas-mediated apoptosis was sensitized in hepatoma cells by cotreatment with sulforaphane, suggesting that sulforaphane can selectively sensitize cells to TRAIL-induced apoptosis but not to apoptosis mediated by other death receptors. We found that sulforaphane treatment significantly up-regulated mRNA and protein levels of DR5, a death receptor of TRAIL. This was accompanied by an increase in the generation of reactive oxygen species (ROS). Pretreatment with N-acetyl-l-cysteine and overexpression of catalase inhibited sulforaphane-induced up-regulation of DR5 and almost completely blocked the cotreatment-induced apoptosis. Furthermore, the sulforaphane-mediated sensitization to TRAIL was efficiently reduced by administration of a blocking antibody or small interfering RNAs for DR5. These results collectively indicate that sulforaphane-induced generation of ROS and the subsequent up-regulation of DR5 are critical for triggering and amplifying TRAIL-induced apoptotic signaling. We also found that sulforaphane can sensitize both Bcl-xL- and Bcl-2-overexpressing hepatoma cells to TRAIL-induced apoptosis, indicating that treatment with a combination of TRAIL and sulforaphane may be a safe strategy for treating resistant hepatomas.
MeSH terms
AnimalsAntineoplastic Combined Chemotherapy Protocols/pharmacology*Apoptosis/drug effectsApoptosis Regulatory Proteins/administration & dosageApoptosis Regulatory Proteins/pharmacology*Carcinoma, Hepatocellular/drug therapy*Carcinoma, Hepatocellular/geneticsCarcinoma, Hepatocellular/metabolismCell Line, TumorDrug Screening Assays, AntitumorDrug SynergismHepatocytes/drug effectsHepatocytes/metabolismHumansInhibitor of Apoptosis Proteins/biosynthesisLiver Neoplasms/drug therapy*Membrane Glycoproteins/administration & dosageMembrane Glycoproteins/pharmacology*Promoter Regions, Genetic/drug effectsProto-Oncogene Proteins c-bcl-2/biosynthesisRatsReactive Oxygen Species/metabolism*Receptors, TNF-Related Apoptosis-Inducing LigandReceptors, Tumor Necrosis Factor/biosynthesisReceptors, Tumor Necrosis Factor/geneticsReceptors, Tumor Necrosis Factor/metabolism*TNF-Related Apoptosis-Inducing LigandThiocyanates/administration & dosageThiocyanates/pharmacology*Transcriptional Activation/drug effectsTumor Necrosis Factor-alpha/administration & dosageTumor Necrosis Factor-alpha/pharmacology*Up-Regulationbcl-X Protein/biosynthesis
DOI
10.1158/0008-5472.CAN-05-1568
PMID
16452234
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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김욱환최경숙
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