title: IL-6 signaling contributes to cisplatin resistance in non-small cell lung cancer via the up-regulation of anti-apoptotic and DNA repair associated molecules.
abstract: Cisplatin-based chemotherapy is currently the most effective treatment regimen for non-small cell lung cancer (NSCLC), but eventually tumor resistance develops which limits its success. The potential implication of IL-6 signaling in the cisplatin resistance of NSCLC was explored by testing whether NSCLC cells with different levels of intracellular IL-6 show different responses to the cytotoxic treatment of cisplatin. When the cisplatin cytotoxicity of the IL-6 knocked down human NSCLC cells (A549IL-6si and H157IL-6si) were compared with their corresponding scramble control cells (A549sc and H157sc), higher cisplatin cytotoxicity was found in IL-6 si cells than sc cells. Subcutaneous xenograft mouse models were developed using a pair of A549sc and A549IL-6si cells. When the tumor grew to about 400 mm2, mice were treated with cisplatin and tumor regression was monitored. Higher tumor regression was detected in the A549IL-6si xenografts compared to A549sc xenografts following cisplatin treatment. Immunostaining study results from tumor tissues also supported this finding. Expression of anti-apoptotic proteins Bcl-2 and Mcl-1 and DNA repair associated molecules ATM, CHK1, TP73, p53, and ERCC1 were significantly up regulated in cisplatin-treated A549sc and H157sc cells, but no increase was detected in A549IL-6si and H157IL-6si cells. Further inhibitor studies revealed that up regulation of these molecules by IL-6 may be through activation of IL-6 downstream signaling pathways like Akt, MAPK, Stat3, and Erk. These results provide potential for combining cisplatin and inhibitors of IL-6 signaling or its downstream signaling pathway as a future therapeutic approach in preventing development of cisplatin resistant NSCLC tumors.
authors: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.|Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.
authors: Shanzhou
authors: S
authors: Duan
authors: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors: Ying
authors: Y
authors: Tsai
authors: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors: Peter
authors: P
authors: Keng
authors: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.
authors: Yongbing
authors: Y
authors: Chen
authors: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors: Soo Ok
authors: SO
authors: Lee
authors: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors: Yuhchyau
authors: Y
authors: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C508600:IL6 protein, human; D015850:Interleukin-6; D002945:Cisplatin
keywords: DNA repair; IL-6; apoptosis; cisplatin resistance; non-small cell lung cancer