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.
Highlights
Epithelial ovarian cancer is the most lethal gynaecological malignancy
We report that WWOX transfection into the non-expressing PEO1 ovarian cancer cell line[21,22] causes sensitisation to paclitaxel, as demonstrated by increased apoptosis following exposure with paclitaxel
The antibody array demonstrated no consistent differences in the expression of apoptosis-related proteins in basal conditions, but upon paclitaxel exposure, a lower B-cell lymphoma-extra large (Bcl-xL)/Bcl-2-associated x (Bax) ratio in WWOX-transfected cells was observed (Figure 1e)
Summary
Epithelial ovarian cancer is the most lethal gynaecological malignancy. Use of platinum and taxane-based chemotherapy result in high response rates, but 70% of patients relapse and develop drug-resistant disease.[1]. We report that WWOX transfection into the non-expressing PEO1 ovarian cancer cell line[21,22] causes sensitisation to paclitaxel, as demonstrated by increased apoptosis following exposure with paclitaxel. This is independent of the antimitotic function of taxanes, but is related to apoptosis because of ER stress induced by paclitaxel. We conclude that (1) both IRE-1 and PERK arms of UPR get activated on exposure of ovarian cancer cells to paclitaxel and active ER stress is a requirement for WWOX-mediated cell death caused by paclitaxel and (2) WWOX expression may predict patient outcome to taxane-based chemotherapy
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