E-Thesis 281 views 101 downloads
The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer / RHIANNON GOULD
Swansea University Author: RHIANNON GOULD
Abstract
Ovarian cancer is the 6th most common cancer in women in the UK. High-grade serous ovarian carcinomas (HGSOC), the most common and aggressive subtype, account for 90% of epithelial ovarian cancers. Whilst most patients initially respond well to chemotherapy, the majority of cases will develop chemot...
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Swansea
2022
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| Institution: | Swansea University |
| Degree level: | Master of Research |
| Degree name: | MSc by Research |
| Supervisor: | Cronin, James G. ; Jones, Nick ; Healy, Gareth D. |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa59819 |
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| Abstract: |
Ovarian cancer is the 6th most common cancer in women in the UK. High-grade serous ovarian carcinomas (HGSOC), the most common and aggressive subtype, account for 90% of epithelial ovarian cancers. Whilst most patients initially respond well to chemotherapy, the majority of cases will develop chemotherapy resistance upon relapse. Recent research has shown chemotherapy resistant cancers to be vulnerable to the induction of ferroptosis, an iron-dependent form of programmed cell death, characterised by the peroxidation of polyunsaturated fatty acids (PUFAs) by lipoxygenases (ALOX) to form lipid peroxides. Niclosamide, an anthelmintic compound, has been shown to induce cytotoxicity in ovarian cancer cells via mitochondrial uncoupling leading to an increase in arachidonic acid (AA). It was hypothesised that this increase in AA provides for an increase in ALOX activity, allowing for ALOX metabolites to activate the NRF2 pathway, an important antioxidant signalling pathway. Crucial protective proteins (SLC7A11 and GPX4) from ferroptosis are confirmed targets of NRF2, suggesting that this pathway could provide resistance to ferroptotic cell death. Cell viability data shows that Niclosamide provided resistance to SLC7A11 positive cells from both Erastin- and RSL3-induced cell death; Erastin and RSL3 are inducers of ferroptosis. Here it was confirmed that Niclosamide acts as a mitochondrial uncoupler using the Mito Stress Test. ALOX12 protein expression was implicated in some cell lines but not others, showing other ALOX isomers need to be investigated. GPX4 protein expression was consistent with cell viability data, indicating its activation as a protective mechanism. NRF2 was also shown to be affected by Niclosamide. The significance of this project is to understand the pathways involving ferroptosis to explore and identify possible targets for novel therapies to induce ferroptosis and treat chemotherapy resistance ovarian cancers. |
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| College: |
Faculty of Medicine, Health and Life Sciences |