Methionine synthase is essential for cancer cell proliferation in physiological folate environments
| Autor: | Mark R. Sullivan, Daniel Rosenberg, Ahmed Ali, Jennifer Roth, Caroline A. Lewis, Tenzin Kunchok, Matthew G. Rees, Lena Joesch-Cohen, Matthew G. Vander Heiden, Alicia M. Darnell, Montana F. Reilly |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Endocrinology
Diabetes and Metabolism 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Gene Expression Regulation Enzymologic Article chemistry.chemical_compound Folic Acid Physiology (medical) Cell Line Tumor Neoplasms Internal Medicine medicine Extracellular Humans Nucleotide Methionine synthase Tetrahydrofolates Cell Proliferation chemistry.chemical_classification Methionine biology Chemistry Cell Biology Gene Expression Regulation Neoplastic Enzyme Methotrexate Biochemistry Drug Resistance Neoplasm Gene Knockdown Techniques Antifolate biology.protein Intracellular medicine.drug |
| Zdroj: | Nat Metab |
| ISSN: | 2522-5812 |
| Popis: | 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. Sullivan and Darnell et al. show that conversion of 5-methyl tetrahydrofolate to tetrahydrofolate by the enzyme methionine synthase is required for tumour growth under physiological folate conditions. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink