Cargando…

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

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 autopha...

Descripción completa

Detalles Bibliográficos
Autores principales: You, Liangkun, Shou, Jiawei, Deng, Danchen, Jiang, Liming, Jing, Zhao, Yao, Junlin, Li, Hongsen, Xie, Jiansheng, Wang, Zhanggui, Pan, Qin, Pan, Hongming, Huang, Wendong, Han, Weidong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741894/
https://www.ncbi.nlm.nih.gov/pubmed/26384345
_version_ 1782414094332067840
author You, Liangkun
Shou, Jiawei
Deng, Danchen
Jiang, Liming
Jing, Zhao
Yao, Junlin
Li, Hongsen
Xie, Jiansheng
Wang, Zhanggui
Pan, Qin
Pan, Hongming
Huang, Wendong
Han, Weidong
author_facet You, Liangkun
Shou, Jiawei
Deng, Danchen
Jiang, Liming
Jing, Zhao
Yao, Junlin
Li, Hongsen
Xie, Jiansheng
Wang, Zhanggui
Pan, Qin
Pan, Hongming
Huang, Wendong
Han, Weidong
author_sort You, Liangkun
collection PubMed
description 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, crizotinib-mediated 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.
format Online
Article
Text
id pubmed-4741894
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-47418942016-03-23 Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines You, Liangkun Shou, Jiawei Deng, Danchen Jiang, Liming Jing, Zhao Yao, Junlin Li, Hongsen Xie, Jiansheng Wang, Zhanggui Pan, Qin Pan, Hongming Huang, Wendong Han, Weidong Oncotarget Research Paper 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, crizotinib-mediated 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. Impact Journals LLC 2015-09-10 /pmc/articles/PMC4741894/ /pubmed/26384345 Text en Copyright: © 2015 You et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
You, Liangkun
Shou, Jiawei
Deng, Danchen
Jiang, Liming
Jing, Zhao
Yao, Junlin
Li, Hongsen
Xie, Jiansheng
Wang, Zhanggui
Pan, Qin
Pan, Hongming
Huang, Wendong
Han, Weidong
Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines
title Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines
title_full Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines
title_fullStr Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines
title_full_unstemmed Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines
title_short Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines
title_sort crizotinib induces autophagy through inhibition of the stat3 pathway in multiple lung cancer cell lines
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741894/
https://www.ncbi.nlm.nih.gov/pubmed/26384345
work_keys_str_mv AT youliangkun crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT shoujiawei crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT dengdanchen crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT jiangliming crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT jingzhao crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT yaojunlin crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT lihongsen crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT xiejiansheng crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT wangzhanggui crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT panqin crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT panhongming crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT huangwendong crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines
AT hanweidong crizotinibinducesautophagythroughinhibitionofthestat3pathwayinmultiplelungcancercelllines