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Targeting iron metabolism in cancer to induce ferroptosis: a type of programmed cell death / Rhiannon Beadman

Swansea University Author: Rhiannon Beadman

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DOI (Published version): 10.23889/SUthesis.66249

Abstract

Cancer patients undergo a number of procedures in order to eradicate tumours. Although cancer patients are often highly responsive to initial treatment, acquired resistance can lead to a relapse in disease. Due to increased metabolism to sustain rapid proliferation, cancer cells are vulnerable to th...

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Published: Swansea, Wales, UK 2024
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Cronin, James G. ; Sheldon, Martin
URI: https://cronfa.swan.ac.uk/Record/cronfa66249
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spelling v2 66249 2024-05-02 Targeting iron metabolism in cancer to induce ferroptosis: a type of programmed cell death f1515bfd40b6dc901824c1bdf8d4a7c4 Rhiannon Beadman Rhiannon Beadman true false 2024-05-02 BMS Cancer patients undergo a number of procedures in order to eradicate tumours. Although cancer patients are often highly responsive to initial treatment, acquired resistance can lead to a relapse in disease. Due to increased metabolism to sustain rapid proliferation, cancer cells are vulnerable to the induction of ferroptotic cell death; a form of programmed cells death-dependent on iron and the accumulation of lipid peroxides. Cancers cells are known to evade ferroptosis through the upregulation of the key enzyme glutathione peroxidase IV (GPX4), which therefore provides a potential therapeutic target. This study used ferroptosis inducers: Erastin and RSL3, which inhibit GPX4 indirectly and directly respectively. A novel ferroptosis-inducing iron oxide nanoparticle was also synthesised for this study. This study used a panel of cancer cell lines: breast, colon, lung and three ovarian cancers which modelled different chemotherapy sensitivities. Ferroptosis was characterised by the accumulation of lipid peroxides and changes in GPX4. Ferroptosis was confirmed after the addition of a lipid peroxide scavenger, which rescued against Erastin and RSL3 induced ferroptotic cell death. Autophagy induction was also investigated to determine the role autophagy regulators may play in ferroptotic induction. Overall, cancer cells were more susceptible to RSL3-induced ferroptotic cell death. Autophagy was induced and inhibited through the activation and inhibition of AMPK, respectively, resulting in changes in ferroptotic induction in the cancer cells, which requires further investigation. Furthermore, the ferroptosis-inducing iron oxide nanoparticles induced cancer cell death, which was characteristic of ferroptosis. Therefore, ferroptosis could be exploited as a therapeutic target for cancer nanotherapy. E-Thesis Swansea, Wales, UK cancer, metabolism, ovarian cancer, breast cancer, colon cancer, lung cancer, melanoma, ferroptosis, RSL3, Erastin, nanoparticles, immunotherapy, autophagy, apoptosis, cancer therapy, nanomedicine, mTOR, AMPK, iron oxide nanoparticles, PEGylation, Ferumoxytol, linoleic acid 20 2 2024 2024-02-20 10.23889/SUthesis.66249 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Cronin, James G. ; Sheldon, Martin Doctoral Ph.D EPSRC doctoral training grant EPSRC doctoral training grant 2024-05-02T16:54:20.6316867 2024-05-02T16:39:29.5581683 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Rhiannon Beadman 1 66249__30250__c707be537e9148c1b13303c868aec14a.pdf Beadman_Rhiannon_PhD_Thesis_Final_Redacted_Signature_Redacted.pdf 2024-05-02T16:48:54.5425608 Output 21006814 application/pdf E-Thesis – open access true Copyright: The Author, Rhiannon P. Beadman, 2024. true eng
title Targeting iron metabolism in cancer to induce ferroptosis: a type of programmed cell death
spellingShingle Targeting iron metabolism in cancer to induce ferroptosis: a type of programmed cell death
Rhiannon Beadman
title_short Targeting iron metabolism in cancer to induce ferroptosis: a type of programmed cell death
title_full Targeting iron metabolism in cancer to induce ferroptosis: a type of programmed cell death
title_fullStr Targeting iron metabolism in cancer to induce ferroptosis: a type of programmed cell death
title_full_unstemmed Targeting iron metabolism in cancer to induce ferroptosis: a type of programmed cell death
title_sort Targeting iron metabolism in cancer to induce ferroptosis: a type of programmed cell death
author_id_str_mv f1515bfd40b6dc901824c1bdf8d4a7c4
author_id_fullname_str_mv f1515bfd40b6dc901824c1bdf8d4a7c4_***_Rhiannon Beadman
author Rhiannon Beadman
author2 Rhiannon Beadman
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publishDate 2024
institution Swansea University
doi_str_mv 10.23889/SUthesis.66249
college_str Faculty of Medicine, Health and Life Sciences
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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 - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description Cancer patients undergo a number of procedures in order to eradicate tumours. Although cancer patients are often highly responsive to initial treatment, acquired resistance can lead to a relapse in disease. Due to increased metabolism to sustain rapid proliferation, cancer cells are vulnerable to the induction of ferroptotic cell death; a form of programmed cells death-dependent on iron and the accumulation of lipid peroxides. Cancers cells are known to evade ferroptosis through the upregulation of the key enzyme glutathione peroxidase IV (GPX4), which therefore provides a potential therapeutic target. This study used ferroptosis inducers: Erastin and RSL3, which inhibit GPX4 indirectly and directly respectively. A novel ferroptosis-inducing iron oxide nanoparticle was also synthesised for this study. This study used a panel of cancer cell lines: breast, colon, lung and three ovarian cancers which modelled different chemotherapy sensitivities. Ferroptosis was characterised by the accumulation of lipid peroxides and changes in GPX4. Ferroptosis was confirmed after the addition of a lipid peroxide scavenger, which rescued against Erastin and RSL3 induced ferroptotic cell death. Autophagy induction was also investigated to determine the role autophagy regulators may play in ferroptotic induction. Overall, cancer cells were more susceptible to RSL3-induced ferroptotic cell death. Autophagy was induced and inhibited through the activation and inhibition of AMPK, respectively, resulting in changes in ferroptotic induction in the cancer cells, which requires further investigation. Furthermore, the ferroptosis-inducing iron oxide nanoparticles induced cancer cell death, which was characteristic of ferroptosis. Therefore, ferroptosis could be exploited as a therapeutic target for cancer nanotherapy.
published_date 2024-02-20T16:54:19Z
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score 11.013148

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