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Phytosphingosine in combination with TRAIL sensitizes cancer cells to TRAIL through synergistic up-regulation of DR4 and DR5.

Authors
Choi, SY; Kim, MJ; Chung, HY; Lee, SJ; Jang, YJ
Citation
Oncology reports, 17(1):175-184, 2007
Journal Title
Oncology reports
ISSN
1021-335X1791-2431
Abstract
Sensitization of cancer cells to TRAIL could improve the effectiveness of TRAIL as an anticancer agent. We explored whether TRAIL in combination with phytosphingosine could sensitize cancer cells to TRAIL. The combined treatment enhanced synergistic apoptotic cell death of Jurkat T cells, compared to TRAIL or phytosphingosine alone. Enhanced apoptosis in response to the combination treatment was associated with caspase-8 activation-mediated Bax and Bak activation and mitochondrial dysfunction. The combination treatment also resulted in synergistic up-regulation of TRAIL receptor R1 (DR4) and R2 (DR5). siRNA targeting of DR5 significantly attenuated the combination treatment-induced caspase-8 activation, mitochondrial dysfunction, and apoptotic cell death. Upon stimulation of cells with the combination treatment, NF-kappaB was activated. Moreover, siRNA targeting of NF-kappaB significantly attenuated the combination treatment-induced DR4 and DR5 expression and receptor-mediated caspase-8 activation. These results indicate that phytosphingosine sensitizes cancer cells to TRAIL through the synergistic up-regulation of DR4 and DR5 in an NF-kappaB-dependent fashion resulting in caspase-8 activation and subsequent mitochondrial dysfunction. These findings support the potential application of combination treatment with TRAIL and phytosphingosine in the treatment of cancers that are less sensitive to TRAIL.
MeSH terms
Antineoplastic Combined Chemotherapy Protocols/pharmacology*Apoptosis/drug effectsApoptosis/physiologyBH3 Interacting Domain Death Agonist Protein/metabolismCarcinoma, Non-Small-Cell Lung/drug therapyCarcinoma, Non-Small-Cell Lung/metabolismCarcinoma, Non-Small-Cell Lung/pathologyCaspase 8/metabolismDrug SynergismEnzyme Activation/drug effectsHumansJurkat CellsLung Neoplasms/drug therapyLung Neoplasms/metabolismLung Neoplasms/pathologyLymphoma, T-Cell/drug therapy*Lymphoma, T-Cell/metabolismLymphoma, T-Cell/pathologyMitochondria/drug effectsMitochondria/physiologyNF-kappa B/metabolismReceptors, TNF-Related Apoptosis-Inducing Ligand/biosynthesis*Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolismReceptors, Tumor Necrosis Factor/biosynthesis*Receptors, Tumor Necrosis Factor/metabolismRecombinant Proteins/administration & dosageRecombinant Proteins/pharmacologySphingosine/administration & dosageSphingosine/analogs & derivatives*Sphingosine/pharmacologyT-Lymphocytes/drug effectsTNF-Related Apoptosis-Inducing Ligand/administration & dosageTNF-Related Apoptosis-Inducing Ligand/pharmacology*Up-Regulation/drug effectsbcl-2 Homologous Antagonist-Killer Protein/metabolismbcl-2-Associated X Protein/metabolism
PMID
17143496
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Journal Papers > School of Medicine / Graduate School of Medicine > Microbiology
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장, 영주
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