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Role of Mitochondrial pyruvate carrier in ovarian cancer progression / MOHAMED FAROOK

Swansea University Author: MOHAMED FAROOK

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DOI (Published version): 10.23889/SUthesis.60124

Abstract

Ovarian cancer is the sixth most common cause of cancer deaths in females in the UK. High-grade serous ovarian cancer (HGSOC) comprises 75% of ovarian epithelial carcinomas. Patients with HGSOC initially respond well to platinum-based chemotherapy, but most relapse with the therapy-resistant disease...

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Published: Swansea 2022
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Cronin, James ; Sheldon, Martin I.
URI: https://cronfa.swan.ac.uk/Record/cronfa60124
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first_indexed 2022-06-01T16:14:51Z
last_indexed 2022-06-02T03:33:01Z
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spelling v2 60124 2022-06-01 Role of Mitochondrial pyruvate carrier in ovarian cancer progression 126d5e686030ac46a1d47e591bedc837 MOHAMED FAROOK MOHAMED FAROOK true false 2022-06-01 Ovarian cancer is the sixth most common cause of cancer deaths in females in the UK. High-grade serous ovarian cancer (HGSOC) comprises 75% of ovarian epithelial carcinomas. Patients with HGSOC initially respond well to platinum-based chemotherapy, but most relapse with the therapy-resistant disease. Cancer cells that adapt to their metabolic microenvironment, known as “metabolic flexibility”, are more likely to proliferate, metastasise, and be resistant to therapy. Mitochondrial pyruvate carrier (MPC) is responsible for transporting pyruvate, generated through glycolysis, into mitochondria to enable oxidative phosphorylation (OXPHOS). Up to 80% of ovarian cancers have deleted MPC1 expression, which correlates strongly with poor prognosis across a wide variety of cancers. Here, I hypothesised that depletion of MPC might force ovarian cancer cells to use glutamine as a fuel source enabling their survival in glucose-limited environments. Using ovarian cancer cell lines characterised as MPC1 lacking PEO1 and PEO4 (derived from the same patient), glutamine-addicted (SKOV3) or glutamine-independent (OVCAR3) as exemplars, the role of MPC1 on ovarian cancer cell metabolism was investigated by stable isotope tracing analysis, quantitative real-time PCR, Western blotting, and metabolic assays. This study revealed, innately MPC1-lacking PEO4 cells are able to utilise OXPHOS from glycolytic pyruvate via MPC2 homodimer. However, MPC1 knockdown in OVCAR3 cells is capable of re-purposing amino acid metabolism and yield TCA cycle intermediates from non-carbohydrate precursors for cancer cell survival and metastasis. Moreover, OVCAR3 cells are able to use proline to compensate for the loss of glutamine under the MPC1-depleted state. Exogenous proline availability to MPC1-depleted cells not just rescued cells under nutrient starvation but also enhanced the ECM development in OVCAR3 cells. It is now evident that the observed >80% deletion of MPC1 in HGSOCs mediates not just cancer proliferation but possibly therapy-resistant tumours via upregulating ECM proteins. Here, I show ovarian cancer cells delete MPC1 to increase amino acid metabolism for the dual advantage of conquering carbon and nitrogen limitations and to exhibit an aggressive phenotype while maintaining a quiescent state TCA cycle. E-Thesis Swansea 1 6 2022 2022-06-01 10.23889/SUthesis.60124 ORCiD identifier: https://orcid.org/0000-0001-9841-0793 COLLEGE NANME COLLEGE CODE Swansea University Cronin, James ; Sheldon, Martin I. Doctoral Ph.D 2024-05-17T16:24:04.6256995 2022-06-01T17:11:17.3348991 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine MOHAMED FAROOK 1 60124__24227__530dd78bffa04f55a2f6ccccba2ea2cb.pdf Farook_Mohamed_R_Y_PhD_Thesis_Final_Redacted_Signature.pdf 2022-06-01T17:22:02.9473953 Output 20069221 application/pdf E-Thesis – open access true 2023-06-01T00:00:00.0000000 Copyright: The author, Mohamed R. Y. Farook, 2022. true eng
title Role of Mitochondrial pyruvate carrier in ovarian cancer progression
spellingShingle Role of Mitochondrial pyruvate carrier in ovarian cancer progression
MOHAMED FAROOK
title_short Role of Mitochondrial pyruvate carrier in ovarian cancer progression
title_full Role of Mitochondrial pyruvate carrier in ovarian cancer progression
title_fullStr Role of Mitochondrial pyruvate carrier in ovarian cancer progression
title_full_unstemmed Role of Mitochondrial pyruvate carrier in ovarian cancer progression
title_sort Role of Mitochondrial pyruvate carrier in ovarian cancer progression
author_id_str_mv 126d5e686030ac46a1d47e591bedc837
author_id_fullname_str_mv 126d5e686030ac46a1d47e591bedc837_***_MOHAMED FAROOK
author MOHAMED FAROOK
author2 MOHAMED FAROOK
format E-Thesis
publishDate 2022
institution Swansea University
doi_str_mv 10.23889/SUthesis.60124
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
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description Ovarian cancer is the sixth most common cause of cancer deaths in females in the UK. High-grade serous ovarian cancer (HGSOC) comprises 75% of ovarian epithelial carcinomas. Patients with HGSOC initially respond well to platinum-based chemotherapy, but most relapse with the therapy-resistant disease. Cancer cells that adapt to their metabolic microenvironment, known as “metabolic flexibility”, are more likely to proliferate, metastasise, and be resistant to therapy. Mitochondrial pyruvate carrier (MPC) is responsible for transporting pyruvate, generated through glycolysis, into mitochondria to enable oxidative phosphorylation (OXPHOS). Up to 80% of ovarian cancers have deleted MPC1 expression, which correlates strongly with poor prognosis across a wide variety of cancers. Here, I hypothesised that depletion of MPC might force ovarian cancer cells to use glutamine as a fuel source enabling their survival in glucose-limited environments. Using ovarian cancer cell lines characterised as MPC1 lacking PEO1 and PEO4 (derived from the same patient), glutamine-addicted (SKOV3) or glutamine-independent (OVCAR3) as exemplars, the role of MPC1 on ovarian cancer cell metabolism was investigated by stable isotope tracing analysis, quantitative real-time PCR, Western blotting, and metabolic assays. This study revealed, innately MPC1-lacking PEO4 cells are able to utilise OXPHOS from glycolytic pyruvate via MPC2 homodimer. However, MPC1 knockdown in OVCAR3 cells is capable of re-purposing amino acid metabolism and yield TCA cycle intermediates from non-carbohydrate precursors for cancer cell survival and metastasis. Moreover, OVCAR3 cells are able to use proline to compensate for the loss of glutamine under the MPC1-depleted state. Exogenous proline availability to MPC1-depleted cells not just rescued cells under nutrient starvation but also enhanced the ECM development in OVCAR3 cells. It is now evident that the observed >80% deletion of MPC1 in HGSOCs mediates not just cancer proliferation but possibly therapy-resistant tumours via upregulating ECM proteins. Here, I show ovarian cancer cells delete MPC1 to increase amino acid metabolism for the dual advantage of conquering carbon and nitrogen limitations and to exhibit an aggressive phenotype while maintaining a quiescent state TCA cycle.
published_date 2022-06-01T16:24:05Z
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score 11.013731

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