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

• 出版年: Molecular Metabolism
• 主要な著者: M. Rufaik Farook, Zack Croxford, Steffan Morgan, Anthony D. Horlock, Amy K. Holt, April Rees, Benjamin J. Jenkins, Carmen Tse, Emma Stanton, D. Mark Davies, Catherine A. Thornton, Nicholas Jones, I. Martin Sheldon, Emma E. Vincent, James G. Cronin
• フォーマット: 論文
• 言語: 英語
• 出版事項: Elsevier 2024-03-01
• 主題: Proline; High grade serous ovarian cancer; PYCR1; PYCR2; PYCR3; Mitochonrial pyruvate carrier
• オンライン･アクセス: http://www.sciencedirect.com/science/article/pii/S2212877824000310

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.