Abstract
Overexpression of the anti-apoptotic protein BCL-2 is frequently observed in small cell lung cancers (SCLC) and is associated with chemoresistance. We examined the signaling pathways involved in upregulation of BCL-2 in SCLC, and whether inhibition of NF-kappaB using the 26S proteasome inhibitor bortezomib had any effect on BCL-2 levels or apoptosis. Mutation of a NF-kappaB site in the BCL-2 promoter reduced promoter activity to less than 20% of the wild-type promoter. Treatment with bortezomib resulted in decreased transcription of the BCL-2 promoter, decreased BCL-2 levels, and induced apoptosis. These data provide the necessary laboratory background for further investigation of bortezomib in the treatment of SCLC.
MeSH terms
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Apoptosis / drug effects*
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Blotting, Western
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Boronic Acids / pharmacology*
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Bortezomib
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Carcinoma, Small Cell / pathology*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Luciferases / metabolism
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Lung Neoplasms / pathology*
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / pharmacology
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Protease Inhibitors / pharmacology*
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Proteasome Endopeptidase Complex
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Proteasome Inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Pyrazines / pharmacology*
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Signal Transduction
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Transcription, Genetic / drug effects
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Tumor Cells, Cultured
Substances
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Boronic Acids
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NF-kappa B
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Protease Inhibitors
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Proteasome Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Pyrazines
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Bortezomib
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Luciferases
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease