Suppression of MTHFD2 in MCF‑7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion

Methylenetetrahydrofolate
dehydrogenase (NAD­(P)+ dependent) 2,
methenyltetrahydrofolate cyclohydrolase (MTHFD2) is a mitochondrial
enzyme involved in folate metabolism. A number of recent studies have
highlighted this enzyme as being highly expressed in many solid tumors,
including breast cancer, and to be correlated with poor survival.
However, the metabolic functions of MTHFD2 in cancer cells have not
been well-defined. To investigate the function of MTHFD2 in breast
cancer cells, we generated and characterized MCF-7 cells with stable
suppression of MTHFD2 expression using a combination of cellular assays
and metabolic profiling. Loss of MTHFD2 caused MCF7 cells to become
glycine auxotrophs, that is, reliant on exogenous glycine, and more
sensitive to exogenous folate depletion. Another prominent metabolic
alteration observed as a consequence of MTHFD2 suppression was a more
glycolytic phenotype, consistent with widespread modifications of
cellular metabolism. Collectively, these data suggest that targeting
MTHFD2 activity is likely to influence multiple metabolic pathways
in breast cancer and could be combined with a range of antimetabolite
therapies.