Methionine synthase is essential for cancer cell proliferation in physiological folate environments
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nihms-1749467.pdf
Description
Accepted version
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1.62 MB
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Author(s)
Sullivan, Mark R
Darnell, Alicia M
Reilly, Montana F
Kunchok, Tenzin
Joesch-Cohen, Lena
Rosenberg, Daniel
Ali, Ahmed
Rees, Matthew G
Roth, Jennifer A
Lewis, Caroline A
Date Issued
2021
Journal
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Citation
Sullivan, Mark R, Darnell, Alicia M, Reilly, Montana F, Kunchok, Tenzin, Joesch-Cohen, Lena et al. 2021. "Methionine synthase is essential for cancer cell proliferation in physiological folate environments." Nature Metabolism, 3 (11).
Version
Author's final manuscript
Abstract
Folate metabolism can be an effective target for cancer treatment. However, standard cell culture conditions utilize folic acid, a non-physiological folate source for most tissues. We find that the enzyme that couples folate and methionine metabolic cycles, methionine synthase, is required for cancer cell proliferation and tumour growth when 5-methyl tetrahydrofolate (THF), the major folate found in circulation, is the extracellular folate source. In such physiological conditions, methionine synthase incorporates 5-methyl THF into the folate cycle to maintain intracellular levels of the folates needed for nucleotide production. 5-methyl THF can sustain intracellular folate metabolism in the absence of folic acid. Therefore, cells exposed to 5-methyl THF are more resistant to methotrexate, an antifolate drug that specifically blocks folic acid incorporation into the folate cycle. Together, these data argue that the environmental folate source has a profound effect on folate metabolism, determining how both folate cycle enzymes and antifolate drugs impact proliferation.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/S42255-021-00486-5
