Methionine synthase supports tumor tetrahydrofolate pools
Wang, J. Z.; Ghergurovich, J. M.; Yang, L.; Rabinowitz, J. D.
Show abstract
Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that methionine synthase is only a minor source of methionine in cell culture, tissues, or xenografted tumors. Instead, methionine synthase is required for cells to avoid folate trapping and assimilate 5-methyl-THF into other folate species. Under conditions of physiological extracellular folates, genetic MTR knockout in tumor cells leads to folate trapping, purine synthesis stalling, nucleotide depletion, and impaired growth in cell culture and as xenografts. These defects are rescued by free folate but not one-carbon unit supplementation. Thus, MTR plays a crucial role in liberating tetrahydrofolate for use in one-carbon metabolism.
Matching journals
The top 11 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Anaplastic Thyroid Cancer Cells Upregulate Mitochondrial One-Carbon Metabolism To Meet Purine Demand, Eliciting A Critical Targetable Vulnerability 95%
- UDP-Glucose 6-Dehydrogenase Knockout Impairs Migration and Decreases in vivo Metastatic Ability of Breast Cancer Cells 94%
- Tumor-associated macrophages confer resistance to chemotherapy (Trifluridine/Tipiracil) in digestive cancers by overexpressing Thymidine Phosphorylase 93%
Similar papers in this journal
- In-vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma 95%
- The extracellular matrix drives guanylate production and protects pancreatic cancer cells from oxaliplatin-induced DNA damage. 94%
- Therapeutic targeting of SLC6A8 creatine transporter inhibits KRAS mutant and wildtype colon cancer and modulates human creatine levels 94%
Similar papers in this journal
- The Origin Of Cysteine and its Catabolism in Mammalian Tissues and Tumors 94%
- PAX3-FOXO1 drives targetable cell state-dependent metabolic vulnerabilities in rhabdomyosarcoma 93%
- NRF2 translation block by inhibition of cap-dependent initiation sensitizes lymphoma cells to ferroptosis and CAR-T immunotherapy 93%
Similar papers in this journal
- Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis 96%
- Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography 93%
- FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.