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Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer

Mohamed Yasim Farook, Zack Croxford, Steffan Morgan, Anthony Horlock Orcid Logo, Amy K. Holt, April Rees Orcid Logo, Benjamin Jenkins, CARMEN TSE, Emma Stanton, D. Mark Davies, Cathy Thornton Orcid Logo, Nick Jones Orcid Logo, Martin Sheldon, Emma E. Vincent, James Cronin Orcid Logo

Molecular Metabolism, Volume: 81

Swansea University Authors: Mohamed Yasim Farook, Anthony Horlock Orcid Logo, April Rees Orcid Logo, Benjamin Jenkins, CARMEN TSE, Emma Stanton, Cathy Thornton Orcid Logo, Nick Jones Orcid Logo, Martin Sheldon, James Cronin Orcid Logo

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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...

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Published in: Molecular Metabolism
ISSN: 2212-8778
Published: Elsevier BV 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa65663
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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. 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spelling v2 65663 2024-02-22 Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer 89d7ded7621e0c475a411db60f6e138b Mohamed Yasim Farook Mohamed Yasim Farook true false 4191b316c42c893bec2cada92597ad44 0000-0001-9580-552X Anthony Horlock Anthony Horlock true false ae088f7f8609d2b2ea4666f9b52b3c15 0000-0002-4408-634X April Rees April Rees true false 90f7cfd66781feba615436189178a528 Benjamin Jenkins Benjamin Jenkins true false 4553a16233155a12bbbd77bc2f484f88 CARMEN TSE CARMEN TSE true false cc0c1a851cdfd303c09e4517a5a35a55 Emma Stanton Emma Stanton true false c71a7a4be7361094d046d312202bce0c 0000-0002-5153-573X Cathy Thornton Cathy Thornton true false 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false ab0f74b794e59cc270c69e63ee1d9748 Martin Sheldon Martin Sheldon true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false 2024-02-22 MEDS 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. Journal Article Molecular Metabolism 81 Elsevier BV 2212-8778 Proline, High grade serous ovarian cancer, PYCR1, PYCR2, PYCR3. Mitochonrial pyruvate carrier, Pyrroline-5-carboxylate reductase. Oncometabolism, Collagen 1 3 2024 2024-03-01 10.1016/j.molmet.2024.101900 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) 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]. 2024-07-15T12:03:25.3071106 2024-02-22T08:17:10.1505284 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Mohamed Yasim Farook 1 Zack Croxford 2 Steffan Morgan 3 Anthony Horlock 0000-0001-9580-552X 4 Amy K. Holt 5 April Rees 0000-0002-4408-634X 6 Benjamin Jenkins 7 CARMEN TSE 8 Emma Stanton 9 D. Mark Davies 10 Cathy Thornton 0000-0002-5153-573X 11 Nick Jones 0000-0003-4846-5117 12 Martin Sheldon 13 Emma E. Vincent 14 James Cronin 0000-0002-0590-9462 15 65663__29856__9973acb146164f6181206552c13ec673.pdf 65663.VOR.pdf 2024-03-26T14:15:23.8516861 Output 3693220 application/pdf Version of Record true Crown Copyright 2024. This is an open access article under the CC BY license. true eng http://creativecommons.org/licenses/by/4.0/
title Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer
spellingShingle Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer
Mohamed Yasim Farook
Anthony Horlock
April Rees
Benjamin Jenkins
CARMEN TSE
Emma Stanton
Cathy Thornton
Nick Jones
Martin Sheldon
James Cronin
title_short Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer
title_full Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer
title_fullStr Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer
title_full_unstemmed Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer
title_sort Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer
author_id_str_mv 89d7ded7621e0c475a411db60f6e138b
4191b316c42c893bec2cada92597ad44
ae088f7f8609d2b2ea4666f9b52b3c15
90f7cfd66781feba615436189178a528
4553a16233155a12bbbd77bc2f484f88
cc0c1a851cdfd303c09e4517a5a35a55
c71a7a4be7361094d046d312202bce0c
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author_id_fullname_str_mv 89d7ded7621e0c475a411db60f6e138b_***_Mohamed Yasim Farook
4191b316c42c893bec2cada92597ad44_***_Anthony Horlock
ae088f7f8609d2b2ea4666f9b52b3c15_***_April Rees
90f7cfd66781feba615436189178a528_***_Benjamin Jenkins
4553a16233155a12bbbd77bc2f484f88_***_CARMEN TSE
cc0c1a851cdfd303c09e4517a5a35a55_***_Emma Stanton
c71a7a4be7361094d046d312202bce0c_***_Cathy Thornton
0fce0f7ddbdbfeb968f4e2f1e3f86744_***_Nick Jones
ab0f74b794e59cc270c69e63ee1d9748_***_Martin Sheldon
9cfd17551c0d1f7438895121e4fbb6e8_***_James Cronin
author Mohamed Yasim Farook
Anthony Horlock
April Rees
Benjamin Jenkins
CARMEN TSE
Emma Stanton
Cathy Thornton
Nick Jones
Martin Sheldon
James Cronin
author2 Mohamed Yasim Farook
Zack Croxford
Steffan Morgan
Anthony Horlock
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
format Journal article
container_title Molecular Metabolism
container_volume 81
publishDate 2024
institution Swansea University
issn 2212-8778
doi_str_mv 10.1016/j.molmet.2024.101900
publisher Elsevier BV
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
active_str 0
description 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.
published_date 2024-03-01T12:03:24Z
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score 11.03559

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