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Overexpression of the Mitochondrial Folate and Glycine– Serine Pathway: a New Determinant of Methotrexate Selectivity in Tumors

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Overexpression of the Mitochondrial Folate and Glycine– Serine Pathway: a New Determinant of Methotrexate Selectivity in Tumors Published OnlineFirst November 7, 2012; DOI: 10.1158/0008-5472.CAN-12-3709 Cancer Perspective Research Overexpression of the Mitochondrial Folate and Glycine– Serine Pathway: A New Determinant of Methotrexate Selectivity in Tumors Alexei Vazquez1, Philip M. Tedeschi2, and Joseph R. Bertino3 Abstract Previous studies have documented the roles of transport via the reduced folate carrier, retention via polyglutamylation, and increased levels of the target enzyme, dihydrofolate reductase in sensitivity to meth- otrexate. Recent studies have shown that the mitochondrial enzymes in the cellular metabolism of serine, folate, and glycine are overexpressed in a subset of human cancers and that their expression is required for tumor maintenance. In this Perspective article, we propose that the expression of mitochondrial enzymes in the metabolism of serine and glycine, in addition to those involved in folate metabolism, are determinants of the response to methotrexate. Furthermore, we show that myc activation in tumors is associated with upregulation of these enzymes. We propose that patients whose tumors show this phenotype will be sensitive to folate antagonists targeting thymidylate or purine biosynthesis. Cancer Res; 73(2); 478–82. Ó2012 AACR. Introduction were not upregulated. Unlike the trifunctional cytosolic Previous studies have documented the roles of transport via enzyme, MTHFD1, that contains methylenetetrahydrofolate the reduced folate carrier (RFC), retention via polyglutamyla- dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and tion, and increased levels of the target enzyme, dihydrofolate formyltetrahydrofolate synthetase activity, the mitochondrial reductase in sensitivity to the folate antagonists methotrexate, enzyme MTHFD2 is a bifunctional enzyme that contains pralatrexate, and pemetrexed (1). Although these factors methylenetetrahydrofolate dehydrogenase and methenyltetra- explain in part why tumor cells are sensitive or resistant to hydrofolate cyclohydrolase activity. Formyltetrahydrofolate antifolates, they do not fully account for selectivity. Two recent synthetase activity is encoded by a separate enzyme, publications have now provided insight about why some MTHFD1L. These enzymes contribute to the synthesis and de novo tumor cells, as compared with normal replicating cells, are use of glycine, methylene THF, and N-10 formyl THF for sensitive to methotrexate: Cancer cells that undergo metabolic purine and thymidylate biosynthesis (Fig. 1). reprogramming and are characterized by rapid proliferation Supporting the importance of the above pathway is the high and upregulate glycine consumption and metabolism are expression of mitochondrial 1-carbon pathway components in potently inhibited by methotrexate, whereas normal cells with embryos. A developmental period marked by high cell prolif- fi similar proliferative rates are not as sensitive. eration rates and embryogenesis requires signi cant amounts The contribution by Jain and colleagues (2) showed that of protein, lipid, and nucleic acid synthesis, of similar nature to metabolic reprogramming that occurs in cancer may lead to neoplastic cells. MTHFD1L was found to be upregulated in higher expression of the mitochondrial glycine biosynthetic mouse embryos, with the mitochondria providing more than pathway and upregulation of mitochondrial folate enzymes 75% of the 1-carbon units present in the cytoplasm used for that include serine hydroxymethyl transferase (SHMT2), purine synthesis and other biosynthetic pathways (3). methylenetetrahydrofolate dehydrogenase (MTHFD2), and MTHFD1L and MTHFD2 are targets of microRNA miR-9, tetrahydrofolate synthetase (MTHFD1L; Fig. 1). The up- which may act as a tumor suppressor in regard to these and regulation of these mitochondrial enzymes correlated with other genes (4). High expression of miR-9 suppresses levels of increased proliferation, whereas the folate cytosolic enzymes MTHFD1L and MTHFD2 and miR-9 has been found to be downregulated in breast cancer cell lines (4). Increasing miR-9 levels or knocking down MTHFD2 both have antiproliferative Authors' Affiliations: 1Center for Systems Biology and Department of and proapoptotic effects in tumor cell lines, which suggests Radiation Oncology, 2Graduate School of Biomedical Sciences and that inhibitors of MTHFD2 may show similar effects. Department of Pharmacology, and 3The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Den- Zhang and colleagues (5) isolated tumor-initiating cells from tistry of New Jersey, New Brunswick, New Jersey primary non–small cell lung cancers (NSCLC) and found that Corresponding Author: Joseph R. Bertino, The Cancer Institute of New upregulation of the enzyme glycine decarboxylase and other Jersey, 195 Little Albany Street, Room 3033, New Brunswick, NJ 08903. glycine–serine enzymes was associated with increased rates of Phone: 732-235-5810; Fax: 732-235-8181; E-mail: [email protected] proliferation and poorer outcome in patients with NSCLC. doi: 10.1158/0008-5472.CAN-12-3709 Remarkably, cDNA of the glycine decarboxylase gene trans- Ó2012 American Association for Cancer Research. formed 3T3 cells. Large increases in the levels of thymidylate 478 Cancer Res; 73(2) January 15, 2013 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst November 7, 2012; DOI: 10.1158/0008-5472.CAN-12-3709 Determinants of Methotrexate Selectivity in Tumors pralatrexate and the thymidylate synthase inhibitors 5-fluoro- Mitochondria Cytoplasm uracil and pemetrexed, show selectivity to rapidly proliferat- ing tumors in patients with overexpression of genes coding (1) Serine Glycine Purine biosynthesis for folate metabolism enzymes. To test this hypothesis, we analyzed in vitro data reported by the Genomics of Drug (2) Sensitivity in Cancer at the Sanger Institute (Hinxton, Cam- THF CH2-THF Thymidylate biosynthesis bridge, UK; ref. 9) to determine whether upregulation of the mitochondrial folate enzymes was correlated with sensitivity (3) ATP to methotrexate, a potent inhibitor of dihydrofolate reductase, CH+-THF and when converted intracellularly to polyglutamates (10), an inhibitor of two enzymes of purine synthesis, phosphoribosyl- (5) ADP (4) glycinamide formyltransferase (GARFT), and phosphoribosy- laminoimidazolecarboxamide formyltransferase (AICART). CHO-THF Purine biosynthesis A strong correlation between increased expression of 7 genes and lower IC50 for methotrexate was observed (Fig. 2a), includ- ing the genes coding for the folate mitochondrial enzymes À4 À3 Figure 1. The role of the mitochondria in the generation of purines and SHMT2 (P ¼ 3.8 Â 10 ) and GLDC (P ¼ 5.4 Â 10 ), as well as À thymidylate for DNA synthesis. Reactions 1, 3, 4, and 5 occur in both the SLC19A1 (coding for the RFC, P ¼ 4.1 Â 10 3), DHFR (P ¼ 3.6 Â À À À mitochondria and the cytoplasm, with reaction 2 limited only to the 10 5–5.4 Â 10 4), TYMS (TS, P ¼ 6.9 Â 10 8), GART (GARFT, À À À mitochondria. Reaction 1 and 2 are catalyzed by SHMT2 and the glycine P ¼ 3.6 Â 10 3–1.7 Â 10 2), and PHGDH (P ¼ 1.5 Â 10 2). cleavage system, respectively. In the cytoplasm, reactions 3, 4, and 5 are carried out by the trifunctional enzyme (MTHFD1); in the mitochondria, 2 These data support the hypothesis that methotrexate and enzymes are required (MTHFD2 catalyzes reactions 3 and 4 and potentially other inhibitors of thymidylate and purine bio- MTHFD1L catalyzes reaction 5). The enzyme 10-formyl tetrahydrofolate synthesis could be used to target cancers with high rates of dehydrogenase (not shown) has been reported to be absent in most proliferation. cancer cells (10). Serine hydroxymethytransferase (1); glycine oxidase complex (2); 5–10 methylene tetrahydrofolate dehydrogenase (3); To provide further evidence, we analyzed a study reporting methenyltetrahydrofolate cyclohydrolase (4); and formyltetrahydrofolate the response of patients with acute lymphoblastic leukemia synthetase (5). (ALL) to methotrexate treatment (11). This study reports the leukemia cell counts before and after treatment together with the leukemia gene expression profiles before treatment. We synthase (TS; ref. 6) and dihydrofolate reductase (DHFR; used the fold change reduction in leukemia cell count as a unpublished data) by transfection of immortalized cells can quantification of sensitivity to methotrexate treatment. A also cause transformation, and these findings are in accord strong correlation was observed between the sensitivity to with the idea that upregulation of nucleotide synthesis is methotrexate treatment and increased expression of the associated with metabolic reprogramming and increased genes coding for the folate mitochondrial enzymes SHMT2 À À tumor cell proliferation. The details of how this increase in (P ¼ 1.6 Â 10 2) and MTHFD2 (P ¼ 3.8 Â 10 2) as well as the À enzymes involved in nucleotide biosynthesis is associated with gene SLC19A1 (P ¼ 1.1 Â 10 2) coding for the RFC (Fig. 2b). malignant transformation are not clear. In the study by Zhang Surprisingly, the expression of DHFR did not correlate with and colleagues (5), the mitochondrial SHMT2 and MTHFD2 the response to methotrexate, underscoring the need to and MTHFD1L enzyme levels were not assessed, and emphasis include the folate mitochondrial enzymes in the investigation was focused on the role of glycine decarboxylase to generate of the mechanisms of response to methotrexate. methylenetetrahydrofolate, the 1-carbon donor
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