MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions

Abstract

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme of the folate-mediated one-carbon metabolism pathway. MTHFD2 has become a highly attractive therapeutic target due to its consistent upregulation in cancer tissues and its major contribution to tumor progression, although it also performs vital functions in proliferating healthy cells. Here, we review the diversity of canonical and non-canonical functions of this key metabolic enzyme under physiological conditions and in carcinogenesis. We provide an overview of its therapeutic potential and describe its regulatory mechanisms. In addition, we discuss the recently described non-canonical functions of MTHFD2 and the mechanistic basis of its oncogenic function. Finally, we speculate on novel therapeutic approaches that take into account subcellular compartmentalization and outline new research directions that would contribute to a better understanding of the fundamental roles of this metabolic enzyme in health and disease.

Fig. 1. One-carbon metabolism is a compartmentalized pathway primarily localized in the cytosol and mitochondria.

ALDH1L1/2, 10-formyltetrahydrofolate dehydrogenase cytosolic (1)/ mitochondrial (2); ATIC, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase; DHF, dihydrofolate; DHFR, dihydrofolate reductase; dTMP, deoxythymidine monophopshate; f-Met, formylmethionine; GART, phosphoribosylglycinamide formyltransferase; MTFMT, mitochondrial methionyl-tRNA formyltransferase; MTHFD1, methylenetetrahydrofolate dehydrogenase cyclohydrolase and formyltetrahydrofolate synthase 1; MTHFD1L, monofunctional formyltetrahydrofolate synthase, mitochondrial; MTHFD2/L, methylenetetrahydrofolate dehydrogenase 2/2-like; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; SHMT1/2, serine hydroxymethyltransferase cytosolic(1)/ mitochondrial (2); THF, tetrahydrofolate; TYMS, thymidylate synthase.

Fig. 2. MTHFD2 catalytic activities in the folate pathway.

MTHFD2 catalyzes the reversible conversion from 5,10-methylene-tetrahydrofolate (THF) to 5,10-methenyl-THF, which is then converted to 10-formyl-THF, by two sequential dehydrogenase and cyclohydrolase steps. NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate. Chemical structures were taken from Kawai et al..

Fig. 3. List of MTHFD2 inhibitors.

Chemical structures were obtained from Yang et al. and Bonagas et al.. In all studies, the half maximal inhibitory concentration (IC50) was obtained by biochemical enzymatic assays. CH cyclohydrolase, DH dehydrogenase, NA not available.

Fig. 4. Transcriptional regulation of MTHFD2.

MTHFD2 upregulation can be promoted by several signaling pathways. Besides, MTHFD2 also induces the activation of some of these signaling pathways. AKT protein kinase B, ATF4 activating transcription factor 4, ERK extracellular signal-regulated kinase, HIF2A hypoxia inducible factor 2α, mTORC1 mammalian target of rapamycin complex 1, PI3K phosphatidylinositol 3-kinase, RTKs receptor tyrosine kinases, TGF-β transforming growth factor β.

Fig. 5. Mechanisms by which MTHFD2 promotes cancer progression.

CDK2 cyclin-dependent kinase 2, EMT epithelial-mesenchymal transition, MTHFD2 methylenetetrahydrofolate dehydrogenase 2/2-like, MTHFR methylenetetrahydrofolate reductase, MTR methionine synthase, NAD nicotinamide adenine dinucleotide, NADP nicotinamide adenine dinucleotide phosphate, PARP3 poly-ADP-ribose polymerase 3, THF tetrahydrofolate.