E-Thesis 364 views 26 downloads
Role of Mitochondrial pyruvate carrier in ovarian cancer progression / MOHAMED FAROOK
Swansea University Author: MOHAMED FAROOK
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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Swansea
2022
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| 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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| 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. 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. |
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| Item Description: |
ORCiD identifier: https://orcid.org/0000-0001-9841-0793 |
| College: |
Faculty of Medicine, Health and Life Sciences |