Oncotarget

Research Papers:

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

Liangkun You, Jiawei Shou, Danchen Deng, Liming Jiang, Zhao Jing, Junlin Yao, Hongsen Li, Jiansheng Xie, Zhanggui Wang, Qin Pan, Hongming Pan, Wendong Huang and Weidong Han _

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Oncotarget. 2015; 6:40268-40282. https://doi.org/10.18632/oncotarget.5592

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Abstract

Liangkun You1,*, Jiawei Shou1,*, Danchen Deng2, Liming Jiang1, Zhao Jing1, Junlin Yao1, Hongsen Li1, Jiansheng Xie3, Zhanggui Wang1, Qin Pan1, Hongming Pan1,3, Wendong Huang4, Weidong Han1,3

1Department of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

2Department of Gynaecology and Obstetrics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

3Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

4Division 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.


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