Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines

// Liangkun You 1,* , Jiawei Shou 1,* , Danchen Deng 2 , Liming Jiang 1 , Zhao Jing 1 , Junlin Yao 1 , Hongsen Li 1 , Jiansheng Xie 3 , Zhanggui Wang 1 , Qin Pan 1 , Hongming Pan 1, 3 , Wendong Huang 4 , Weidong Han 1, 3 1 Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 2 Department of Gynaecology and Obstetrics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 3 Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 4 Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA * These authors have contributed equally to this work Correspondence to: Weidong Han, e-mail: hanwd@zju.edu.cn Hongming Pan, e-mail: panhongming@zju.edu.cn Wendong Huang, e-mail: whuang@coh.org Keywords: crizotinib, autophagy, STAT3, lung cancer Received: April 14, 2015 Accepted: August 19, 2015 Published: September 10, 2015 ABSTRACT Autophagy is an evolutionarily conserved survival pathway in eukaryote and is frequently upregulated in cancer cells after chemotherapy or targeted therapy. Thus induction of autophagy has emerged as a drug resistance mechanism. In this study, we found that crizotinib induced a high level of autophagy in lung cancer cells through inhibition of STAT3. Ectopic expression of wild-type or constitutive activated STAT3 significantly suppressed the effect of crizotinib on autophagy. Interestingly, crizotinibmediated inhibition of STAT3 is in a step-wise manner. Firstly it inhibited cytoplasmic STAT3, which leads to the phosphorylation of EIF2A, then inhibited nuclear STAT3, which leads to the downregulation of BCL-2. Cell death induced by crizotinib was greatly enhanced after the inhibition of autophagy by the pharmacological inhibitors or shRNAs against Beclin-1. Moreover, the autophagy inhibitor HCQ significantly augmented the anti-tumor effect of crizotinib in a mouse xenograft model. In conclusion, crizotinib can induce cytoprotective autophagy by suppression of STAT3 in lung cancer cells. Thus, autophagy inhibition represents a promising approach to improve the efficacy of crizotinib in the treatment of targeted lung cancer patients.