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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.

Original publication

DOI

10.1021/acs.jproteome.6b00188

Type

Journal article

Journal

Journal of proteome research

Publication Date

08/2016

Volume

15

Pages

2618 - 2625

Addresses

Department of Cytogenetics and Genomics, Cyprus Institute of Neurology and Genetics , Nicosia, Cyprus.

Keywords

Humans, Folic Acid, Aminohydrolases, Methenyltetrahydrofolate Cyclohydrolase, Methylenetetrahydrofolate Dehydrogenase (NADP), Glycine, Neoplasm Proteins, Gene Expression Regulation, Enzymologic, Glycolysis, Metabolic Networks and Pathways, Metabolome, Gene Knockdown Techniques, MCF-7 Cells, Multifunctional Enzymes