Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer

Abstract

Metabolic remodeling is now widely regarded as a hallmark of cancer, but it is not clear whether individual metabolic strategies are frequently exploited by many tumours. Here we compare messenger RNA profiles of 1,454 metabolic enzymes across 1,981 tumours spanning 19 cancer types to identify enzymes that are consistently differentially expressed. Our meta-analysis recovers established targets of some of the most widely used chemotherapeutics, including dihydrofolate reductase, thymidylate synthase and ribonucleotide reductase, while also spotlighting new enzymes, such as the mitochondrial proline biosynthetic enzyme PYCR1. The highest scoring pathway is mitochondrial one-carbon metabolism and is centred on MTHFD2. MTHFD2 RNA and protein are markedly elevated in many cancers and correlated with poor survival in breast cancer. MTHFD2 is expressed in the developing embryo, but is absent in most healthy adult tissues, even those that are proliferating. Our study highlights the importance of mitochondrial compartmentalization of one-carbon metabolism in cancer and raises important therapeutic hypotheses.

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

“…The shMTHFD2 cells examined here could still grow in the absence of glycine (albeit at a slower rate), although it is not clear whether that is due to residual MTHFD2 activity in these cells, the activity of other enzymes such as 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Fig.3). Supplementation of cell culture media with glycine was also unable to rescue cancer cells after RNAi silencing of MTHFD2 11 . The question therefore arises as to why MCF-7 cells with suppressed MTHFD2 are rendered dependent on exogenous glycine.…”

“…In a separate study, investigation of 1,454 metabolic enzymes in 1,981 human tumors found MTHFD2 to be the most consistently over-expressed 11 . This study also found that MTHFD2 was not present in normal proliferating cells, but appeared to be specific to proliferating transformed cells.…”

“…Recent studies have found a significant association between mRNA expression 10,11 and protein expression of MTHFD2 in large cohorts of breast cancer patients 13 .…”

Targeting MTHFD2 in acute myeloid leukemia

“…Additionally, SHMT2 was found to drive glioma cell proliferation in the presence of ischemia, making the cells sensitive to inhibition of the glycine cleavage system (Kim et al, 2015). In an analysis of differentially expressed mRNA in cancer tissues, Nilsson et al (2014) identified enzymes of the one-carbon folate pathway to be among the most differentially expressed metabolic enzymes in cancer compared with normal cells, with MTH FD2 ranking at the top of the list. In addition, MTH FD2 expression correlated with poor survival in patients with breast cancer (Liu et al, 2014;Nilsson et al, 2014).…”

“…1 B). The role of folate-mediated one-carbon metabolism in cancer, especially in the mitochondrial compartment, has been a subject of renewed interest (Jain et al, 2012;Nilsson et al, 2014). A recent publication has highlighted the mitochondrial enzyme involved in one-carbon folate metabolism, MTHFD2, as the most differentially expressed enzyme in cancer cells compared with normal cells (Nilsson et al, 2014).…”