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The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer / RHIANNON GOULD

Swansea University Author: RHIANNON GOULD

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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 chemot...

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Published: Swansea 2022
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
first_indexed 2022-04-13T15:38:55Z
last_indexed 2022-04-14T03:32:00Z
id cronfa59819
recordtype RisThesis
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spelling 2022-04-13T17:40:04.0709024 v2 59819 2022-04-13 The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer f51d0b15abf12473dfe2a0f942a6fa98 RHIANNON GOULD RHIANNON GOULD true false 2022-04-13 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. E-Thesis Swansea 13 4 2022 2022-04-13 COLLEGE NANME COLLEGE CODE Swansea University Cronin, James G. ; Jones, Nick ; Healy, Gareth D. Master of Research MSc by Research 2022-04-13T17:40:04.0709024 2022-04-13T16:32:29.2699932 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine RHIANNON GOULD 1 59819__23841__61399c028d1c4f8586241e4bb7eb145a.pdf Gould_Rhiannon_MSc_Research_Thesis_Final_Redacted_Signature.pdf 2022-04-13T16:47:57.9445930 Output 2889911 application/pdf E-Thesis – open access true Copyright: The author, Rhiannon Gould, 2022. true eng
title The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer
spellingShingle The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer
RHIANNON GOULD
title_short The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer
title_full The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer
title_fullStr The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer
title_full_unstemmed The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer
title_sort The role of lipoxygenases in evasion of ferroptotic programmed cell death in ovarian cancer
author_id_str_mv f51d0b15abf12473dfe2a0f942a6fa98
author_id_fullname_str_mv f51d0b15abf12473dfe2a0f942a6fa98_***_RHIANNON GOULD
author RHIANNON GOULD
author2 RHIANNON GOULD
format E-Thesis
publishDate 2022
institution Swansea University
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description 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.
published_date 2022-04-13T14:19:07Z
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score 11.048194

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