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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741894/ https://www.ncbi.nlm.nih.gov/pubmed/26384345 |
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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 |
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