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Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer
,
Amy K. Holt,
April Rees ,
Benjamin Jenkins,
CARMEN TSE,
Emma Stanton,
D. Mark Davies,
Cathy Thornton ,
Nick Jones ,
Martin Sheldon ,
Emma E. Vincent,
James Cronin
Molecular Metabolism, Volume: 81
Swansea University Authors:
Mohamed Rufaik Yasim Farook, Anthony Horlock , April Rees , Benjamin Jenkins, CARMEN TSE, Emma Stanton, Cathy Thornton , Nick Jones , Martin Sheldon , James Cronin
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DOI (Published version): 10.1016/j.molmet.2024.101900
Abstract
The pyruvate transporter MPC1 (mitochondrial pyruvate carrier 1) acts as a tumour-suppressor, loss of which correlates with a pro-tumorigenic phenotype and poor survival in several tumour types. In high-grade serous ovarian cancers (HGSOC), patients display copy number loss of MPC1 in around 78% of...
| Published in: | Molecular Metabolism |
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| ISSN: | 2212-8778 |
| Published: |
Elsevier BV
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa65663 |
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| Abstract: |
The pyruvate transporter MPC1 (mitochondrial pyruvate carrier 1) acts as a tumour-suppressor, loss of which correlates with a pro-tumorigenic phenotype and poor survival in several tumour types. In high-grade serous ovarian cancers (HGSOC), patients display copy number loss of MPC1 in around 78% of cases and reduced MPC1 mRNA expression. To explore the metabolic effect of reduced expression, we demonstrate that depleting MPC1 in HGSOC cell lines drives expression of key proline biosynthetic genes; PYCR1, PYCR2 and PYCR3, and biosynthesis of proline. We show that altered proline metabolism underpins cancer cell proliferation, reactive oxygen species (ROS) production, and type I and type VI collagen formation in ovarian cancer cells. Furthermore, exploring The Cancer Genome Atlas, we discovered the PYCR3 isozyme to be highly expressed in a third of HGSOC patients, which was associated with more aggressive disease and diagnosis at a younger age. Taken together, our study highlights that targeting proline metabolism is a potential therapeutic avenue for the treatment of HGSOC. |
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| Keywords: |
Proline, High grade serous ovarian cancer, PYCR1, PYCR2, PYCR3. Mitochonrial pyruvate carrier, Pyrroline-5-carboxylate reductase. Oncometabolism, Collagen |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This work here was in part supported by grants awarded by St David's Medical Foundation, Registered Charity No. 1122688; the Welsh Government in support of the C81844/C81845 ACCELERATE (Welsh Health Innovation Technology Accelerator) project. The results published here are part based upon data generated by The Cancer Genome Atlas (TCGA) Research Network: https://www.cancer.gov/tcga. EEV was supported by Cancer Research UK [grant number C18281/A29019]. NJ was supported by a New Investigator Research Grant from the Medical Research Council, United Kingdom [grant number MR/X000095/1]. |