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.
Division of Cancer, Department of Surgery and Cancer, Imperial College London , Hammersmith Hospital, London, U.K.|Department of Cytogenetics and Genomics, Cyprus Institute of Neurology and Genetics , Nicosia, Cyprus.
Costas
C
Koufaris
Division of Cancer, Department of Surgery and Cancer, Imperial College London , Hammersmith Hospital, London, U.K.
Suchira
S
Gallage
Division of Cancer, Department of Surgery and Cancer, Imperial College London , Hammersmith Hospital, London, U.K.
Tianlai
T
Yang
Division of Cancer, Department of Surgery and Cancer, Imperial College London , Hammersmith Hospital, London, U.K.
Chung-Ho
CH
Lau
Division of Cancer, Department of Surgery and Cancer, Imperial College London , Hammersmith Hospital, London, U.K.
Gabriel N
GN
Valbuena
Division of Cancer, Department of Surgery and Cancer, Imperial College London , Hammersmith Hospital, London, U.K.
Hector C
HC
Keun
D000619:Aminohydrolases / Q000172:deficiency*; D005492:Folic Acid / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D005998:Glycine / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D061986:MCF-7 Cells; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D045064:Methenyltetrahydrofolate Cyclohydrolase / Q000172:deficiency*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000172:deficiency*; D064251:Multifunctional Enzymes / Q000172:deficiency*; D009363:Neoplasm Proteins
C000624959:MTHFD2 protein, human; D064251:Multifunctional Enzymes; D009363:Neoplasm Proteins; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D045064:Methenyltetrahydrofolate Cyclohydrolase; D005998:Glycine
MCF-7; MTHFD2; cancer; folate; glycine; glycolysis; metabolomics; shRNA