Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Green, A. C., Marttila, P., Kiweler, N., Chalkiadaki, C., Wiita, E., Cookson, V., Lesur, A., Eiden, K., Bernardin, F., Vallin, K. S. A., Borhade, S., Long, M., Ghahe, E. K., Jiménez-Alonso, J. J., Jemth, A., Loseva, O., Mortusewicz, O., Meyers, M., Viry, E., Johansson, A. I., Hodek, O., Homan, E., Bonagas, N., Ramos, L., Sandberg, L., Frödin, M., Moussay, E., Slipicevic, A., Letellier, E., Paggetti, J., Sørensen, C. S., Helleday, T., Henriksson, M., & Meiser, J. Nature Metabolism, 5(4):642–659, April, 2023. Number: 4 Publisher: Nature Publishing Group![Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex 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.
@article{green_formate_2023,
title = {Formate overflow drives toxic folate trapping in {MTHFD1} inhibited cancer cells},
volume = {5},
copyright = {2023 The Author(s)},
issn = {2522-5812},
url = {https://www.nature.com/articles/s42255-023-00771-5},
doi = {10.1038/s42255-023-00771-5},
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.},
language = {en},
number = {4},
urldate = {2023-05-05},
journal = {Nature Metabolism},
author = {Green, Alanna C. and Marttila, Petra and Kiweler, Nicole and Chalkiadaki, Christina and Wiita, Elisée and Cookson, Victoria and Lesur, Antoine and Eiden, Kim and Bernardin, François and Vallin, Karl S. A. and Borhade, Sanjay and Long, Maeve and Ghahe, Elahe Kamali and Jiménez-Alonso, Julio J. and Jemth, Ann-Sofie and Loseva, Olga and Mortusewicz, Oliver and Meyers, Marianne and Viry, Elodie and Johansson, Annika I. and Hodek, Ondřej and Homan, Evert and Bonagas, Nadilly and Ramos, Louise and Sandberg, Lars and Frödin, Morten and Moussay, Etienne and Slipicevic, Ana and Letellier, Elisabeth and Paggetti, Jérôme and Sørensen, Claus Storgaard and Helleday, Thomas and Henriksson, Martin and Meiser, Johannes},
month = apr,
year = {2023},
note = {Number: 4
Publisher: Nature Publishing Group},
keywords = {Cancer metabolism, Cell death, Metabolism},
pages = {642--659},
}
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