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Capsaicin sensitizes malignant glioma cells to TRAIL-mediated apoptosis via DR5 upregulation and survivin downregulation.

Authors
Kim, JY; Kim, EH; Kim, SU; Kwon, TK; Choi, KS
Citation
Carcinogenesis, 31(3):367-375, 2010
Journal Title
Carcinogenesis
ISSN
0143-33341460-2180
Abstract
Capsaicin, a pungent ingredient of red chili peppers, has been reported to possess antitumor activities. Here, we show that subtoxic doses of capsaicin effectively sensitize multiple malignant glioma cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Although TRAIL alone mediated partial proteolytic processing of procaspase-3 in glioma cells, cotreatment with capsaicin and TRAIL efficiently restored complete activation of caspases. We found that treatment of various gliomas with capsaicin significantly upregulated DR5, a death receptor of TRAIL, and downregulated the caspase inhibitor survivin. The induction of DR5 was mediated by CHOP/GADD153. The reduction in survivin protein level was associated with downregulation of cyclin B and Cdc2 expression, suggesting that inhibition of Cdc2 activity might contribute to capsaicin-induced survivin downregulation. Taken together, these results indicate that the activity of capsaicin toward DR5 and survivin contributes to the amplification of caspase cascades, thereby restoring TRAIL sensitivity in malignant glioma cells. Interestingly, normal astrocytes were resistant to combined treatment with capsaicin and TRAIL. Neither capsaicin-induced DR5 upregulation/survivin downregulation nor the partial processing of procaspase-3 by TRAIL was induced in astrocytes. Thus, a combined regimen using capsaicin and TRAIL may provide a safe and effective strategy for treating malignant gliomas.
MeSH terms
Apoptosis/*drug effectsAstrocytes/cytology/drug effectsCapsaicin/*pharmacologyCaspases/*physiologyCell Line, Tumor/cytology/drug effectsCells, Cultured/cytology/drug effectsCyclin B/biosynthesis/geneticsDown-Regulation/drug effectsGlioma/*pathologyHumansMicrotubule-Associated Proteins/*biosynthesis/genetics/physiologyNeoplasm Proteins/*biosynthesis/genetics/physiologyRNA, Small Interfering/pharmacologyReceptors, TNF-Related Apoptosis-Inducing Ligand/antagonists &Recombinant Fusion Proteins/physiologyRecombinant Proteins/pharmacologySignal Transduction/drug effectsTNF-Related Apoptosis-Inducing Ligand/*pharmacologyTranscription Factor CHOP/physiologyUp-Regulation/drug effects
DOI
10.1093/carcin/bgp298
PMID
19939880
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Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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