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WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response
There are clear gaps in our understanding of genes and pathways through which cancer cells facilitate survival strategies as they become chemoresistant. Paclitaxel is used in the treatment of many cancers, but development of drug resistance is common. Along with being an antimitotic agent paclitaxel...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550887/ https://www.ncbi.nlm.nih.gov/pubmed/28749468 http://dx.doi.org/10.1038/cddis.2017.346 |
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author | Janczar, Szymon Nautiyal, Jaya Xiao, Yi Curry, Edward Sun, Mingjun Zanini, Elisa Paige, Adam JW Gabra, Hani |
author_facet | Janczar, Szymon Nautiyal, Jaya Xiao, Yi Curry, Edward Sun, Mingjun Zanini, Elisa Paige, Adam JW Gabra, Hani |
author_sort | Janczar, Szymon |
collection | PubMed |
description | There are clear gaps in our understanding of genes and pathways through which cancer cells facilitate survival strategies as they become chemoresistant. Paclitaxel is used in the treatment of many cancers, but development of drug resistance is common. Along with being an antimitotic agent paclitaxel also activates endoplasmic reticulum (ER) stress. Here, we examine the role of WWOX (WW domain containing oxidoreductase), a gene frequently lost in several cancers, in mediating paclitaxel response. We examine the ER stress-mediated apoptotic response to paclitaxel in WWOX-transfected epithelial ovarian cancer (EOC) cells and following siRNA knockdown of WWOX. We show that WWOX-induced apoptosis following exposure of EOC cells to paclitaxel is related to ER stress and independent of the antimitotic action of taxanes. The apoptotic response to ER stress induced by WWOX re-expression could be reversed by WWOX siRNA in EOC cells. We report that paclitaxel treatment activates both the IRE-1 and PERK kinases and that the increase in paclitaxel-mediated cell death through WWOX is dependent on active ER stress pathway. Log-rank analysis of overall survival (OS) and progression-free survival (PFS) in two prominent EOC microarray data sets (Tothill and The Cancer Genome Atlas), encompassing ~800 patients in total, confirmed clinical relevance to our findings. High WWOX mRNA expression predicted longer OS and PFS in patients treated with paclitaxel, but not in patients who were treated with only cisplatin. The association of WWOX and survival was dependent on the expression level of glucose-related protein 78 (GRP78), a key ER stress marker in paclitaxel-treated patients. We conclude that WWOX sensitises EOC to paclitaxel via ER stress-induced apoptosis, and predicts clinical outcome in patients. Thus, ER stress response mechanisms could be targeted to overcome chemoresistance in cancer. |
format | Online Article Text |
id | pubmed-5550887 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-55508872017-08-14 WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response Janczar, Szymon Nautiyal, Jaya Xiao, Yi Curry, Edward Sun, Mingjun Zanini, Elisa Paige, Adam JW Gabra, Hani Cell Death Dis Original Article There are clear gaps in our understanding of genes and pathways through which cancer cells facilitate survival strategies as they become chemoresistant. Paclitaxel is used in the treatment of many cancers, but development of drug resistance is common. Along with being an antimitotic agent paclitaxel also activates endoplasmic reticulum (ER) stress. Here, we examine the role of WWOX (WW domain containing oxidoreductase), a gene frequently lost in several cancers, in mediating paclitaxel response. We examine the ER stress-mediated apoptotic response to paclitaxel in WWOX-transfected epithelial ovarian cancer (EOC) cells and following siRNA knockdown of WWOX. We show that WWOX-induced apoptosis following exposure of EOC cells to paclitaxel is related to ER stress and independent of the antimitotic action of taxanes. The apoptotic response to ER stress induced by WWOX re-expression could be reversed by WWOX siRNA in EOC cells. We report that paclitaxel treatment activates both the IRE-1 and PERK kinases and that the increase in paclitaxel-mediated cell death through WWOX is dependent on active ER stress pathway. Log-rank analysis of overall survival (OS) and progression-free survival (PFS) in two prominent EOC microarray data sets (Tothill and The Cancer Genome Atlas), encompassing ~800 patients in total, confirmed clinical relevance to our findings. High WWOX mRNA expression predicted longer OS and PFS in patients treated with paclitaxel, but not in patients who were treated with only cisplatin. The association of WWOX and survival was dependent on the expression level of glucose-related protein 78 (GRP78), a key ER stress marker in paclitaxel-treated patients. We conclude that WWOX sensitises EOC to paclitaxel via ER stress-induced apoptosis, and predicts clinical outcome in patients. Thus, ER stress response mechanisms could be targeted to overcome chemoresistance in cancer. Nature Publishing Group 2017-07 2017-07-27 /pmc/articles/PMC5550887/ /pubmed/28749468 http://dx.doi.org/10.1038/cddis.2017.346 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Janczar, Szymon Nautiyal, Jaya Xiao, Yi Curry, Edward Sun, Mingjun Zanini, Elisa Paige, Adam JW Gabra, Hani WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response |
title | WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response |
title_full | WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response |
title_fullStr | WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response |
title_full_unstemmed | WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response |
title_short | WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response |
title_sort | wwox sensitises ovarian cancer cells to paclitaxel via modulation of the er stress response |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550887/ https://www.ncbi.nlm.nih.gov/pubmed/28749468 http://dx.doi.org/10.1038/cddis.2017.346 |
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