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Targeting Ferroptosis in Tuberous Sclerosis Cell Line Models / TASMIA TAHSIN

Swansea University Author: TASMIA TAHSIN

DOI (Published version): 10.23889/SUthesis.69835

Abstract

Ferroptosis, an iron-dependent cell death mechanism characterized by oxidative damage to phospholipids and subsequent membrane damage, presents a promising target for cancer therapy. The TSC1-TSC2 complex is crucial in cellular signalling, regulating cell growth, proliferation, and metabolism. Mutat...

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Published: Swansea, Wales, UK 2025
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Conlan, Steve ; Gonzalez, Deya ; Davies, Mark ; Tee, Andrew ; Hughes, Stephen Fôn
URI: https://cronfa.swan.ac.uk/Record/cronfa69835
first_indexed 2025-06-27T11:57:13Z
last_indexed 2025-06-28T07:58:32Z
id cronfa69835
recordtype RisThesis
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spelling 2025-06-27T13:22:49.9548684 v2 69835 2025-06-27 Targeting Ferroptosis in Tuberous Sclerosis Cell Line Models 3ec7c3fcd951d3f00f6b41d35aafd03c TASMIA TAHSIN TASMIA TAHSIN true false 2025-06-27 Ferroptosis, an iron-dependent cell death mechanism characterized by oxidative damage to phospholipids and subsequent membrane damage, presents a promising target for cancer therapy. The TSC1-TSC2 complex is crucial in cellular signalling, regulating cell growth, proliferation, and metabolism. Mutations or loss of TSC2 lead to hyperactivation of mTORC1, implicated in various cancers. This research aimed to elucidate the role of TSC2 loss in ferroptosis and its contribution to drug resistance in TSC2-cell line models, potentially guiding the development of new therapeutic strategies. Cytotoxicity testing within this study revealed that Tsc2-deficient cells have greater resistance to ferroptosis induction compared to Tsc2-positive cells. Notably, inhibition of mTORC1 did not reverse this resistance, whereas NRF2 antioxidant pathway inhibition and AMPK activation did, suggesting that resistance operates through mTORC1-independent pathways. Biochemical analysis identified altered ferroptosis markers in Tsc2-deficient cells, such as ROS-mediated lipid peroxidation, GPX4, GSH, and labile iron pools as key factors in this resistance. Further investigations into NRF2 revealed significantly elevated nuclear translocation upon ferroptosis induction in Tsc2-deficient cells during ferroptosis induction, identifying the NRF2 pathway as a potential mediator of resistance. qPCR and RNAseq analyses confirmed significant dysregulation of NRF2 and its target genes between TSC2-deficient and TSC2-expressing tumours. Additionally, inhibition of ferroptosis suppressor protein 1 (FSP1) also counteracted the cell death resistance in Tsc2-deficient cells. These cells displayed a fourfold increase in mRNA levels of FSP1, which significantly enhanced their resistance to ferroptosis. Overall, this thesis establishes that the loss of TSC2 confers resistance to ferroptosis through mechanisms that are independent of mTORC1 overactivation but dependent on NRF2 activation. This study also provides a deeper understanding of ferroptosis and additional cellular signalling pathways, such as those involving ROS regulation, lipid peroxidation, and iron metabolism, within the context of TSC2 loss. These insights will guide the development of future therapeutic strategies targeting ferroptosis in TSC2-deficient cancers. E-Thesis Swansea, Wales, UK Cell biology, Cancer, Cell signalling, Biochemistry 17 6 2025 2025-06-17 10.23889/SUthesis.69835 COLLEGE NANME COLLEGE CODE Swansea University Conlan, Steve ; Gonzalez, Deya ; Davies, Mark ; Tee, Andrew ; Hughes, Stephen Fôn Doctoral Ph.D KESS 2 Knowledge Economy Skills Scholarships KESS 2 Knowledge Economy Skills Scholarships 2025-06-27T13:22:49.9548684 2025-06-27T12:52:03.3717573 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science TASMIA TAHSIN 1 69835__34613__582a491dc77948508d70361f99758e39.pdf Tahsin_Tasmia_PhD_Thesis_Final_Cronfa.pdf 2025-06-27T13:02:01.0555468 Output 4243836 application/pdf E-Thesis – open access true Copyright: The Author, Tasmia Tahsin, 2025. true eng
title Targeting Ferroptosis in Tuberous Sclerosis Cell Line Models
spellingShingle Targeting Ferroptosis in Tuberous Sclerosis Cell Line Models
TASMIA TAHSIN
title_short Targeting Ferroptosis in Tuberous Sclerosis Cell Line Models
title_full Targeting Ferroptosis in Tuberous Sclerosis Cell Line Models
title_fullStr Targeting Ferroptosis in Tuberous Sclerosis Cell Line Models
title_full_unstemmed Targeting Ferroptosis in Tuberous Sclerosis Cell Line Models
title_sort Targeting Ferroptosis in Tuberous Sclerosis Cell Line Models
author_id_str_mv 3ec7c3fcd951d3f00f6b41d35aafd03c
author_id_fullname_str_mv 3ec7c3fcd951d3f00f6b41d35aafd03c_***_TASMIA TAHSIN
author TASMIA TAHSIN
author2 TASMIA TAHSIN
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publishDate 2025
institution Swansea University
doi_str_mv 10.23889/SUthesis.69835
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 - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description Ferroptosis, an iron-dependent cell death mechanism characterized by oxidative damage to phospholipids and subsequent membrane damage, presents a promising target for cancer therapy. The TSC1-TSC2 complex is crucial in cellular signalling, regulating cell growth, proliferation, and metabolism. Mutations or loss of TSC2 lead to hyperactivation of mTORC1, implicated in various cancers. This research aimed to elucidate the role of TSC2 loss in ferroptosis and its contribution to drug resistance in TSC2-cell line models, potentially guiding the development of new therapeutic strategies. Cytotoxicity testing within this study revealed that Tsc2-deficient cells have greater resistance to ferroptosis induction compared to Tsc2-positive cells. Notably, inhibition of mTORC1 did not reverse this resistance, whereas NRF2 antioxidant pathway inhibition and AMPK activation did, suggesting that resistance operates through mTORC1-independent pathways. Biochemical analysis identified altered ferroptosis markers in Tsc2-deficient cells, such as ROS-mediated lipid peroxidation, GPX4, GSH, and labile iron pools as key factors in this resistance. Further investigations into NRF2 revealed significantly elevated nuclear translocation upon ferroptosis induction in Tsc2-deficient cells during ferroptosis induction, identifying the NRF2 pathway as a potential mediator of resistance. qPCR and RNAseq analyses confirmed significant dysregulation of NRF2 and its target genes between TSC2-deficient and TSC2-expressing tumours. Additionally, inhibition of ferroptosis suppressor protein 1 (FSP1) also counteracted the cell death resistance in Tsc2-deficient cells. These cells displayed a fourfold increase in mRNA levels of FSP1, which significantly enhanced their resistance to ferroptosis. Overall, this thesis establishes that the loss of TSC2 confers resistance to ferroptosis through mechanisms that are independent of mTORC1 overactivation but dependent on NRF2 activation. This study also provides a deeper understanding of ferroptosis and additional cellular signalling pathways, such as those involving ROS regulation, lipid peroxidation, and iron metabolism, within the context of TSC2 loss. These insights will guide the development of future therapeutic strategies targeting ferroptosis in TSC2-deficient cancers.
published_date 2025-06-17T05:29:13Z
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