These authors contributed equally to this work.
Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation
Article first published online: 8 SEP 2014
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Volume 105, Issue 9, pages 1220–1227, September 2014
How to Cite
Cancer Sci 105 (2014) 1220–1227
State Key Laboratory of Oncogenes and Related Genes (90-14-05). National Natural Science Foundation of China (81273203).
- Issue published online: 23 SEP 2014
- Article first published online: 8 SEP 2014
- Accepted manuscript online: 2 JUL 2014 10:06PM EST
- Manuscript Accepted: 27 JUN 2014
- Manuscript Revised: 13 JUN 2014
- Manuscript Received: 10 MAR 2014
- State Key Laboratory of Oncogenes and Related Genes. Grant Number: 90-14-05
- National Natural Science Foundation of China. Grant Number: 81273203
- Ataxia-telangiectasia mutated;
- interleukin 6;
- multiple drug resistance;
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.