Upregulation of Bcl-x and Bfl-1 as a potential mechanism of chemoresistance, which can be overcome by NF-kappaB inhibition.
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.
Cheng
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Department of Microbiology and Molecular Genetics, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, University of California Los Angeles, 90095, USA.
Lee
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Li
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Parks
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Cheng
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D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020672:I-kappa B Proteins; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015778:Minor Histocompatibility Antigens; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha; D004318:Doxycycline