Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Abstract

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a ‘folate trap’. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.

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Item Type:	Article
Authors/Creators:	Green, A.C. https://orcid.org/0000-0002-0175-1485 Marttila, P. https://orcid.org/0000-0002-0115-8067 Kiweler, N. https://orcid.org/0000-0001-7493-703X Chalkiadaki, C. Wiita, E. Cookson, V. Lesur, A. Eiden, K. Bernardin, F. https://orcid.org/0000-0002-6329-5542 Vallin, K.S.A. Borhade, S. Long, M. Ghahe, E.K. Jiménez-Alonso, J.J. Jemth, A.-S. https://orcid.org/0000-0002-7550-1833 Loseva, O. Mortusewicz, O. https://orcid.org/0000-0002-4290-4994 Meyers, M. Viry, E. Johansson, A.I. https://orcid.org/0000-0001-5000-1288 Hodek, O. https://orcid.org/0000-0001-8307-9575 Homan, E. Bonagas, N. https://orcid.org/0000-0001-7336-4065 Ramos, L. https://orcid.org/0000-0002-3808-6853 Sandberg, L. Frödin, M. Moussay, E. https://orcid.org/0000-0002-0879-8067 Slipicevic, A. Letellier, E. https://orcid.org/0000-0001-8242-9393 Paggetti, J. https://orcid.org/0000-0001-9460-5876 Sørensen, C.S. Helleday, T. https://orcid.org/0000-0002-7384-092X Henriksson, M. https://orcid.org/0000-0002-2230-4887 Meiser, J. https://orcid.org/0000-0002-9093-6210
Copyright, Publisher and Additional Information:	© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Cancer metabolism; Cell death; Metabolism
Dates:	Published: April 2023 Published (online): 3 April 2023 Accepted: 28 February 2023
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	24 Apr 2023 15:48
Last Modified:	04 May 2023 01:24
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s42255-023-00771-5
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:198483

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Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

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