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

Farook, M. Rufaik, Croxford, Zack, Morgan, Steffan, Horlock, Anthony D., Holt, Amy K., Rees, April, Jenkins, Benjamin J., Tse, Carmen, Stanton, Emma, Davies, D. Mark, Thornton, Catherine A., Jones, Nicholas, Sheldon, I. Martin, Vincent, Emma E. and Cronin, James G. 2023. Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer. Molecular Metabolism 81 , 101900. 10.1016/j.molmet.2024.101900

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Elsevier
ISSN:	2212-8778
Date of First Compliant Deposit:	25 February 2025
Date of Acceptance:	9 February 2024
Last Modified:	03 Mar 2025 14:15
URI:	https://orca.cardiff.ac.uk/id/eprint/176347

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