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

// Shanzhou Duan 1, 2 , Ying Tsai 1 , Peter Keng 1 , Yongbing Chen 2 , Soo Ok Lee 1 , Yuhchyau Chen 1 1 Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA 2 Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China Correspondence to: Yuhchyau Chen, e-mail: Yuhchyau_Chen@urmc.rochester.edu Soo Ok Lee, e-mail: Soook_Lee@urmc.rochester.edu Keywords: non-small cell lung cancer, IL-6, cisplatin resistance, apoptosis, DNA repair Received: May 26, 2015 Accepted: July 17, 2015 Published: July 30, 2015 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 mm 2 , 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.