Abstract
In A549 human lung adenocarcinoma cells, we found that TNF-alpha and several commonly used chemotherapeutic agents upregulated the expression of Bcl-x and/or Bfl-1/A1 through an NF-kappaB-dependent pathway. While parental A549 cells were resistant to the cytotoxic effects of both TNF-alpha and chemotherapy agents, NF-kappaB-blocked A549 cells were sensitized to both. Expression of either Bcl-x or Bfl-1/A1 in the NF-kappaB-deficient cells at physiological levels provided differential protection against TNF-alpha and chemotherapeutic treatment. These studies provide a potential mechanism for the phenomenon of chemotherapy-induced chemoresistance, and also reveal a potential strategy by which chemoresistance can be overcome.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology*
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Antineoplastic Agents / pharmacology*
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology
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Doxycycline / pharmacology
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Drug Resistance, Neoplasm / genetics*
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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I-kappa B Proteins*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Minor Histocompatibility Antigens
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / physiology
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / drug effects
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Protein Biosynthesis
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Proteins / genetics
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Proteins / physiology*
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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RNA, Messenger / biosynthesis
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RNA, Neoplasm / biosynthesis
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Receptors, Tumor Necrosis Factor / drug effects
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Receptors, Tumor Necrosis Factor / physiology
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Recombinant Fusion Proteins / physiology
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Transfection
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Tumor Necrosis Factor-alpha / pharmacology*
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bcl-X Protein
Substances
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Antineoplastic Agents
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BCL2-related protein A1
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BCL2L1 protein, human
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DNA-Binding Proteins
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I-kappa B Proteins
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Minor Histocompatibility Antigens
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NF-kappa B
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NFKBIA protein, human
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Neoplasm Proteins
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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RNA, Neoplasm
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Receptors, Tumor Necrosis Factor
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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bcl-X Protein
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NF-KappaB Inhibitor alpha
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Doxycycline