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Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine
The combination of platinum and gemcitabine is one of the standard regimens in the treatment of advanced lung squamous carcinoma (LSC). Resistance to gemcitabine is main barrier to the successful treatment of LSC. In this study, we showed that suppression of the Fanconi anemia (FA) pathway increased...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678185/ https://www.ncbi.nlm.nih.gov/pubmed/29118324 http://dx.doi.org/10.1038/s41598-017-15172-4 |
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author | Dai, Chun-Hua Wang, Yi Chen, Ping Jiang, Qian Lan, Ting Li, Mei-Yu Su, Jin-Yu Wu, Yan Li, Jian |
author_facet | Dai, Chun-Hua Wang, Yi Chen, Ping Jiang, Qian Lan, Ting Li, Mei-Yu Su, Jin-Yu Wu, Yan Li, Jian |
author_sort | Dai, Chun-Hua |
collection | PubMed |
description | The combination of platinum and gemcitabine is one of the standard regimens in the treatment of advanced lung squamous carcinoma (LSC). Resistance to gemcitabine is main barrier to the successful treatment of LSC. In this study, we showed that suppression of the Fanconi anemia (FA) pathway increased the sensitivity of two LSC cell lines SK-MES-1 and KLN205 to gemcitabine. Moreover, we found that the CHK1 pathway and the FA pathway are functionally compensatory in the repair of DNA damage in the LSC cell lines. Inactivation of one of the two pathways led to DNA damage, triggering compensatory activation of other pathway. Furthermore, we demonstrated that FANCD2 depletion combined with CHK1 inhibitor MK-8776 significantly potentiated the cytotoxicity of gemcitabine to the two LSC cell lines, compared to individual FANCD2 depletion or MK-8776 treatment. The enhanced effect of gemcitabine-chemosensitization was accompanied by loss of DNA repair function and accumulation of DNA single strand breaks and double strand breaks, in parallel with obvious increase of caspase-3 dependent apoptosis. Our results indicate that the enhancement effect of FANCD2 depletion combined with CHK1 inhibitor in sensitizing the LCS cells to gemcitabine supports the FA pathway and CHK1 as two therapeutic targets for improvement of anti-tumor regimens in treatment of LSC. |
format | Online Article Text |
id | pubmed-5678185 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56781852017-11-17 Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine Dai, Chun-Hua Wang, Yi Chen, Ping Jiang, Qian Lan, Ting Li, Mei-Yu Su, Jin-Yu Wu, Yan Li, Jian Sci Rep Article The combination of platinum and gemcitabine is one of the standard regimens in the treatment of advanced lung squamous carcinoma (LSC). Resistance to gemcitabine is main barrier to the successful treatment of LSC. In this study, we showed that suppression of the Fanconi anemia (FA) pathway increased the sensitivity of two LSC cell lines SK-MES-1 and KLN205 to gemcitabine. Moreover, we found that the CHK1 pathway and the FA pathway are functionally compensatory in the repair of DNA damage in the LSC cell lines. Inactivation of one of the two pathways led to DNA damage, triggering compensatory activation of other pathway. Furthermore, we demonstrated that FANCD2 depletion combined with CHK1 inhibitor MK-8776 significantly potentiated the cytotoxicity of gemcitabine to the two LSC cell lines, compared to individual FANCD2 depletion or MK-8776 treatment. The enhanced effect of gemcitabine-chemosensitization was accompanied by loss of DNA repair function and accumulation of DNA single strand breaks and double strand breaks, in parallel with obvious increase of caspase-3 dependent apoptosis. Our results indicate that the enhancement effect of FANCD2 depletion combined with CHK1 inhibitor in sensitizing the LCS cells to gemcitabine supports the FA pathway and CHK1 as two therapeutic targets for improvement of anti-tumor regimens in treatment of LSC. Nature Publishing Group UK 2017-11-08 /pmc/articles/PMC5678185/ /pubmed/29118324 http://dx.doi.org/10.1038/s41598-017-15172-4 Text en © The Author(s) 2017 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Dai, Chun-Hua Wang, Yi Chen, Ping Jiang, Qian Lan, Ting Li, Mei-Yu Su, Jin-Yu Wu, Yan Li, Jian Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine |
title | Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine |
title_full | Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine |
title_fullStr | Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine |
title_full_unstemmed | Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine |
title_short | Suppression of the FA pathway combined with CHK1 inhibitor hypersensitize lung cancer cells to gemcitabine |
title_sort | suppression of the fa pathway combined with chk1 inhibitor hypersensitize lung cancer cells to gemcitabine |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678185/ https://www.ncbi.nlm.nih.gov/pubmed/29118324 http://dx.doi.org/10.1038/s41598-017-15172-4 |
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