Abstract
Although it is known that ataxia-telangiectasia mutated (ATM) and interleukin 6 (IL-6) contribute to multiple drug resistance (MDR) in tumor chemotherapy, the exact role of ATM activation in MDR resulting from increased IL-6 expression is still unclear. In the present study, we demonstrate that the activation of the ATM-NF-kappaB pathway, resulting from increased IL-6 expression, plays a central role in augmented chemoresistance in lung cancer cell lines. This result was supported by the increased expressions of Bcl-2, Mcl-1, Bcl-xl, and the upregulation of MDR-associated protein ABCG2. The higher level of IL-6 reveals not only higher ATM/NF-kappaB activity but also increased expressions of ABCG2, Bcl-2, Mcl-1 and Bcl-xl. Most importantly, lung cancer cells themselves upregulated IL-6 secretion by activating the p38/NF-kappaB pathway through treatment with cisplatin and camptothecin. Taken together, these findings demonstrate that chemotherapeutic agents increase IL-6 expression, hence activating the ATM/NF-kappaB pathway, augmenting anti-apoptotic protein expression and contributing to MDR. This indicates that both IL-6 and ATM are potential targets for the treatment of chemotherapeutic resistance in lung cancer.
Keywords:
Ataxia-telangiectasia mutated; NF-kappaB; chemotherapy; interleukin 6; multiple drug resistance.
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Antineoplastic Agents / pharmacology
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Ataxia Telangiectasia Mutated Proteins / metabolism*
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Camptothecin / pharmacology
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Cell Line, Tumor
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Cisplatin / pharmacology
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Drug Resistance, Neoplasm*
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Gene Expression
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Gene Expression Regulation, Neoplastic
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Humans
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Imidazoles / pharmacology
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Interleukin-6 / physiology*
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Lung Neoplasms
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Nitriles / pharmacology
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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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Pyridines / pharmacology
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Sulfones / pharmacology
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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3-(4-methylphenylsulfonyl)-2-propenenitrile
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antineoplastic Agents
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BCL2L1 protein, human
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Imidazoles
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Interleukin-6
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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NF-kappa B
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Neoplasm Proteins
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Nitriles
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Proto-Oncogene Proteins c-bcl-2
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Pyridines
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Sulfones
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bcl-X Protein
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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p38 Mitogen-Activated Protein Kinases
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SB 203580
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Cisplatin
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Camptothecin