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Downregulation of vimentin expression increased drug resistance in ovarian cancer cells
Cisplatin and other platinum-based drugs have been widely used in the treatment of ovarian cancer, but most patients acquire the drug resistance that greatly compromises the efficacy of drugs. Understanding the mechanism of drug resistance is important for finding new therapeutic approaches. In the...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216767/ https://www.ncbi.nlm.nih.gov/pubmed/27322682 http://dx.doi.org/10.18632/oncotarget.9970 |
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author | Huo, Yi Zheng, Zhiguo Chen, Yuling Wang, Qingtao Zhang, Zhenyu Deng, Haiteng |
author_facet | Huo, Yi Zheng, Zhiguo Chen, Yuling Wang, Qingtao Zhang, Zhenyu Deng, Haiteng |
author_sort | Huo, Yi |
collection | PubMed |
description | Cisplatin and other platinum-based drugs have been widely used in the treatment of ovarian cancer, but most patients acquire the drug resistance that greatly compromises the efficacy of drugs. Understanding the mechanism of drug resistance is important for finding new therapeutic approaches. In the present study, we found that the expression of vimentin was downregulated in drug-resistant ovarian cancer cell lines A2780-DR and HO-8910 as compared to their respective control cells. Overexpression of vimentin in A2780-DR cells markedly increased their sensitivity to cisplatin, whereas knockdown of vimentin in A2780, HO-8910-PM and HO-8910 cells increased the resistance to cisplatin, demonstrating that vimentin silencing enhanced cisplatin resistance in ovarian cancer cells. Quantitative proteomic analysis identified 95 differentially expressed proteins between the vimentin silenced A2780 cells (A2780-VIM-KN) and the control cells, in which downregulation of endocytic proteins and the upregulation of exocytotic proteins CHMP2B and PDZK1 were proposed to contribute the decreased cisplatin accumulation in vimentin knockdown cells. Silencing of vimentin induced upregulation of cancer stem cell markers and both A2780-DR and A2780-VIM-KN cells were more facile to form spheroids than control cells under serum-free culture condition. Our results also revealed that vimentin knockdown increased the 14-3-3 mediated retention of Cdc25C in the cytoplasm, leading to inactivation of Cdk1 and the prolonged G2 phase arrest that allowed the longer period of time for cells to repair cisplatin-damaged DNA. Taken together, we demonstrated that vimentin silencing enhanced cells' resistance to cisplatin via prolonged G2 arrest and increased exocytosis, suggesting that vimentin is a potential target for treatment of drug resistant ovarian cancer. |
format | Online Article Text |
id | pubmed-5216767 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-52167672017-01-15 Downregulation of vimentin expression increased drug resistance in ovarian cancer cells Huo, Yi Zheng, Zhiguo Chen, Yuling Wang, Qingtao Zhang, Zhenyu Deng, Haiteng Oncotarget Research Paper Cisplatin and other platinum-based drugs have been widely used in the treatment of ovarian cancer, but most patients acquire the drug resistance that greatly compromises the efficacy of drugs. Understanding the mechanism of drug resistance is important for finding new therapeutic approaches. In the present study, we found that the expression of vimentin was downregulated in drug-resistant ovarian cancer cell lines A2780-DR and HO-8910 as compared to their respective control cells. Overexpression of vimentin in A2780-DR cells markedly increased their sensitivity to cisplatin, whereas knockdown of vimentin in A2780, HO-8910-PM and HO-8910 cells increased the resistance to cisplatin, demonstrating that vimentin silencing enhanced cisplatin resistance in ovarian cancer cells. Quantitative proteomic analysis identified 95 differentially expressed proteins between the vimentin silenced A2780 cells (A2780-VIM-KN) and the control cells, in which downregulation of endocytic proteins and the upregulation of exocytotic proteins CHMP2B and PDZK1 were proposed to contribute the decreased cisplatin accumulation in vimentin knockdown cells. Silencing of vimentin induced upregulation of cancer stem cell markers and both A2780-DR and A2780-VIM-KN cells were more facile to form spheroids than control cells under serum-free culture condition. Our results also revealed that vimentin knockdown increased the 14-3-3 mediated retention of Cdc25C in the cytoplasm, leading to inactivation of Cdk1 and the prolonged G2 phase arrest that allowed the longer period of time for cells to repair cisplatin-damaged DNA. Taken together, we demonstrated that vimentin silencing enhanced cells' resistance to cisplatin via prolonged G2 arrest and increased exocytosis, suggesting that vimentin is a potential target for treatment of drug resistant ovarian cancer. Impact Journals LLC 2016-06-13 /pmc/articles/PMC5216767/ /pubmed/27322682 http://dx.doi.org/10.18632/oncotarget.9970 Text en Copyright: © 2016 Huo 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 Huo, Yi Zheng, Zhiguo Chen, Yuling Wang, Qingtao Zhang, Zhenyu Deng, Haiteng Downregulation of vimentin expression increased drug resistance in ovarian cancer cells |
title | Downregulation of vimentin expression increased drug resistance in ovarian cancer cells |
title_full | Downregulation of vimentin expression increased drug resistance in ovarian cancer cells |
title_fullStr | Downregulation of vimentin expression increased drug resistance in ovarian cancer cells |
title_full_unstemmed | Downregulation of vimentin expression increased drug resistance in ovarian cancer cells |
title_short | Downregulation of vimentin expression increased drug resistance in ovarian cancer cells |
title_sort | downregulation of vimentin expression increased drug resistance in ovarian cancer cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216767/ https://www.ncbi.nlm.nih.gov/pubmed/27322682 http://dx.doi.org/10.18632/oncotarget.9970 |
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