WWOX is a tumour suppressor gene, as demonstrated by increased neoplasia incidence in Wwox-knock-out animals, and is frequently disrupted in human cancers. WWOX expression reconstitution
abolishes xenograft growth of lung, pancreatic, breast, ovarian and prostate cancer cells. The tumoursuppressive
function of WWOX is suggested to be related to pro-apoptotic effects or interactions with
potentially oncogenic transcription factors leading to their cytoplasmic sequestration and trans-activity
inhibition. In physiology WWOX might be involved in metabolism.
Our group demonstrated that WWOX reconstitution in ovarian cancer cells inhibits xenograft growth
but this was not accompanied by altered in vitro growth or apoptosis rates. Rather, WWOX
transfection reduced cancer cell adhesion to extracellular matrix due to reduction of integrin α3
binding. Additionally, our group postulated that natural polymorphic variants of WWOX are linked to
ovarian cancer clinicopathological features.
The hypotheses behind this work were that WWOX regulates gene expression or promotes apoptosis
in ovarian cancer. Further, this project aimed at confirming the associations of WWOX
polymorphisms.
I demonstrate no link between WWOX status and the subcellular localization of putative WWOX-binding
transcription factors or the expression of their target genes in ovarian cancer cells. The
phenotypic consequences of WWOX expression manipulation do not appear to be explained by
transcriptional changes.
I show that WWOX increases apoptosis rates in ovarian cancer cells exposed to the chemotherapy
agent paclitaxel, but not cisplatin. This is independent of the anti-mitotic function of taxanes and
unrelated to integrin regulation. Rather, WWOX promotes cell death during taxane-induced
endoplasmic reticulum stress. I propose WWOX-driven cell death during endoplasmic reticulum stress
might be also linked to anti-tumorigenic effects in vivo.
A validation study did not confirm the link between WWOX genetic variants and ovarian cancer
pathology. There is also no link between WWOX polymorphisms and bone metabolism, a trait
affected in WWOX-knock-out animals.