• Chemotherapy response and the role of the WWOX tumour suppressor

      Farooq, Haroon (University of BedfordshireUniversity of Bedfordshire, 2017-08)
      Paclitaxel is a widely used chemotherapy drug for the treatment of multiple cancers. Paclitaxel works by inhibiting the disassembly of microtubules. Besides the role of paclitaxel in mitotic arrest, many studies suggest that paclitaxel could initiate apoptosis by activating ER-stress pathways. Cisplatin, another chemotherapy drug is also used for the treatment of solid tumours. It works by forming adducts with the structure of DNA leading to cell cycle arrest, DNA damage and apoptosis. These two chemotherapy drugs have different mechanisms of killing tumour cells, but they are often combined to give greater effect. WWOX is a tumour suppressor in many cancers. It has been shown that WWOX promotes apoptosis and suppresses in vivo tumorigenesis, but its function remains unclear. Here in my study I hypothesize that ER-stress is an important part of paclitaxel response in cancer cells, and the WWOX tumour suppressor is important in mediating paclitaxel induced ER-stress response. I also hypothesize that WWOX is important in mediating the apoptotic response to cisplatin. My results show that paclitaxel could not induce ER stress in multiple cancer cells lines, and WWOX did not affect the cytotoxic action of paclitaxel. I show some evidence that ER-stress may influence survival in ovarian cancer patients, but this is independent of the effect of WWOX expression. I show that WWOX is not important for cisplatin response since cisplatin suppresses the expression of WWOX. This effect may relate to its location at a common fragile site since cisplatin also down-regulates another fragile site-associated gene FHIT. However, I also show the apparent involvement of NF-kB2 and PAR2 transcription factors in the down regulation of WWOX. These findings increase our understanding of the unintended effects of chemotherapy treatments.