WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response

Szymon Janczar
,
Jaya Nautiyal
,
Yi Xiao
,
Edward Curry
,
Mingjun Sun
,
Elisa Zanini

Medical University of Łódź
,
Imperial College Healthcare NHS Trust
,
AstraZeneca

Research Output:

Contribution to journal

Article

Peer-review

Open access

Sustainable Development Goals

SDG 3 Good Health and Well

Abstract

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.

Publication Information

Output type

Research Output:

Contribution to journal

Article

Peer-review

Original language

English

Pages from-to (Number of pages)

Pages e2955

Journal (Volume, Issue Number)

Cell Death and Disease (Volume 8, Issue 7)

Publication milestones

Published - 27/07/2017

Publication status

Published - 27/07/2017

Publication IDs

handle.net: 10547/623632
Scopus: 85046420834

Access to documents

10.1038/cddis.2017.346

final published version

Final published version, 1.88 MB

License:CC BY

https://www.nature.com/articles/cddis2017346

Final published version

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