title: Overexpression of the mitochondrial folate and glycine-serine pathway: a new determinant of methotrexate selectivity in tumors.
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 methotrexate. 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.
authors.affiliation: Center for Systems Biology and Department of Radiation Oncology, Graduate School of Biomedical Sciences, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Vazquez
authors.forename: Philip M
authors.initials: PM
authors.lastname: Tedeschi
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
mesh_terms: D001692:Biological Transport; D005492:Folic Acid / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D012694:Serine / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D005493:Folic Acid Antagonists; D012694:Serine; D005492:Folic Acid; D005998:Glycine; D008727:Methotrexate