title: Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation.
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.
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, China.
authors.forename: Hong Qiong
authors.initials: HQ
authors.lastname: Yan
authors.forename: Xiao Bo
authors.initials: XB
authors.lastname: Huang
authors.forename: Shi Zhong
authors.initials: SZ
authors.lastname: Ke
authors.forename: Yi Na
authors.initials: YN
authors.lastname: Jiang
authors.forename: Yue Hua
authors.initials: YH
authors.lastname: Zhang
authors.forename: Yi Nan
authors.initials: YN
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Feng Guang
authors.initials: FG
authors.lastname: Gao
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000502:physiology*; D008175:Lung Neoplasms; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D007093:Imidazoles; D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D013450:Sulfones; D051020:bcl-X Protein; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D002945:Cisplatin; D002166:Camptothecin
keywords: Ataxia-telangiectasia mutated; NF-kappaB; chemotherapy; interleukin 6; multiple drug resistance