Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation

Cancer Sci. 2014 Sep;105(9):1220-7. doi: 10.1111/cas.12478. Epub 2014 Sep 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Antineoplastic Agents / pharmacology
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-6 / physiology*
  • Lung Neoplasms
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Nitriles / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyridines / pharmacology
  • Sulfones / pharmacology
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • BCL2L1 protein, human
  • Imidazoles
  • Interleukin-6
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • NF-kappa B
  • Neoplasm Proteins
  • Nitriles
  • Proto-Oncogene Proteins c-bcl-2
  • Pyridines
  • Sulfones
  • bcl-X Protein
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580
  • Cisplatin
  • Camptothecin