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Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib
BACKGROUND: The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated. METHODS: The effect of autop...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188165/ https://www.ncbi.nlm.nih.gov/pubmed/35690866 http://dx.doi.org/10.1186/s13046-022-02390-6 |
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author | Lyu, Xin Zeng, Lizhong Shi, Jie Ming, Zongjuan Li, Wei Liu, Boxuan Chen, Yang Yuan, Bo Sun, Ruiying Yuan, Jingyan Zhao, Nannan Yang, Xia Chen, Guoan Yang, Shuanying |
author_facet | Lyu, Xin Zeng, Lizhong Shi, Jie Ming, Zongjuan Li, Wei Liu, Boxuan Chen, Yang Yuan, Bo Sun, Ruiying Yuan, Jingyan Zhao, Nannan Yang, Xia Chen, Guoan Yang, Shuanying |
author_sort | Lyu, Xin |
collection | PubMed |
description | BACKGROUND: The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated. METHODS: The effect of autophagy in icotinib resistance was examined using a series of in vitro and in vivo assays. The results above were further verified in biopsy specimens of lung cancer patients before and after icotinib or gefitinib treatment. RESULTS: Icotinib increased ATG3, ATG5, and ATG7 expression, but without affecting Beclin-1, VPS34 and ATBG14 levels in icotinib-resistant lung cancer cells. Autophagy blockade by 3-MA or silencing Beclin-1 had no effects on resistance to icotinib. CQ effectively restored lung cancer cell sensitivity to icotinib in vitro and in vivo. Notably, aberrantly activated STAT3 and highly expressed FOXM1 were required for autophagy induced by icotinib, without the involvement of AMPK/mTOR pathway in this process. Alterations of STAT3 activity using genetic and/or pharmacological methods effectively affected FOXM1 and ATG7 levels increased by icotinib, with altering autophagy and icotinib-mediated apoptosis in resistant cells. Furthermore, silencing FOXM1 impaired up-regulated ATG7 induced by STAT3-CA and icotinib. STAT3/FOXM1 signalling blockade also reversed resistance to icotinib in vivo. Finally, we found a negative correlation between STAT3/FOXM1/ATG7 signalling activity and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment efficacy in patients undergoing EGFR-TKIs treatment. CONCLUSIONS: Our findings support that STAT3/FOXM1/ATG7 signalling-induced autophagy is a novel mechanism of resistance to icotinib, and provide insights into potential clinical values of ATG7-dependent autophagy in icotinib treatment. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02390-6. |
format | Online Article Text |
id | pubmed-9188165 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-91881652022-06-12 Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib Lyu, Xin Zeng, Lizhong Shi, Jie Ming, Zongjuan Li, Wei Liu, Boxuan Chen, Yang Yuan, Bo Sun, Ruiying Yuan, Jingyan Zhao, Nannan Yang, Xia Chen, Guoan Yang, Shuanying J Exp Clin Cancer Res Research BACKGROUND: The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated. METHODS: The effect of autophagy in icotinib resistance was examined using a series of in vitro and in vivo assays. The results above were further verified in biopsy specimens of lung cancer patients before and after icotinib or gefitinib treatment. RESULTS: Icotinib increased ATG3, ATG5, and ATG7 expression, but without affecting Beclin-1, VPS34 and ATBG14 levels in icotinib-resistant lung cancer cells. Autophagy blockade by 3-MA or silencing Beclin-1 had no effects on resistance to icotinib. CQ effectively restored lung cancer cell sensitivity to icotinib in vitro and in vivo. Notably, aberrantly activated STAT3 and highly expressed FOXM1 were required for autophagy induced by icotinib, without the involvement of AMPK/mTOR pathway in this process. Alterations of STAT3 activity using genetic and/or pharmacological methods effectively affected FOXM1 and ATG7 levels increased by icotinib, with altering autophagy and icotinib-mediated apoptosis in resistant cells. Furthermore, silencing FOXM1 impaired up-regulated ATG7 induced by STAT3-CA and icotinib. STAT3/FOXM1 signalling blockade also reversed resistance to icotinib in vivo. Finally, we found a negative correlation between STAT3/FOXM1/ATG7 signalling activity and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment efficacy in patients undergoing EGFR-TKIs treatment. CONCLUSIONS: Our findings support that STAT3/FOXM1/ATG7 signalling-induced autophagy is a novel mechanism of resistance to icotinib, and provide insights into potential clinical values of ATG7-dependent autophagy in icotinib treatment. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02390-6. BioMed Central 2022-06-11 /pmc/articles/PMC9188165/ /pubmed/35690866 http://dx.doi.org/10.1186/s13046-022-02390-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Lyu, Xin Zeng, Lizhong Shi, Jie Ming, Zongjuan Li, Wei Liu, Boxuan Chen, Yang Yuan, Bo Sun, Ruiying Yuan, Jingyan Zhao, Nannan Yang, Xia Chen, Guoan Yang, Shuanying Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib |
title | Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib |
title_full | Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib |
title_fullStr | Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib |
title_full_unstemmed | Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib |
title_short | Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib |
title_sort | essential role for stat3/foxm1/atg7 signaling-dependent autophagy in resistance to icotinib |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188165/ https://www.ncbi.nlm.nih.gov/pubmed/35690866 http://dx.doi.org/10.1186/s13046-022-02390-6 |
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