title: Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype.
abstract: Folate coenzymes are involved in biochemical reactions of one-carbon transfer, and deficiency of this vitamin impairs cellular proliferation, migration, and survival in many cell types. Here, the effect of folate restriction on mammary cancer was evaluated using three distinct breast cancer subtypes differing in their aggressiveness and metastatic potential: noninvasive basal-like (E-Wnt), invasive but minimally metastatic claudin-low (M-Wnt), and highly metastatic claudin-low (metM-Wntliver) cell lines, each derived from the same pool of MMTV-Wnt-1 transgenic mouse mammary tumors. NMR-based metabolomics was used to quantitate 41 major metabolites in cells grown in folate-free medium versus standard medium. Each cell line demonstrated metabolic reprogramming when grown in folate-free medium. In E-Wnt, M-Wnt, and metM-Wntlivercells, 12, 29, and 25 metabolites, respectively, were significantly different (P < 0.05 and at least 1.5-fold change). The levels of eight metabolites (aspartate, ATP, creatine, creatine phosphate, formate, serine, taurine and β-alanine) were changed in each folate-restricted cell line. Increased glucose, decreased lactate, and inhibition of glycolysis, cellular proliferation, migration, and invasion occurred in M-Wnt and metM-Wntlivercells (but not E-Wnt cells) grown in folate-free versus standard medium. These effects were accompanied by altered levels of several folate-metabolizing enzymes, indicating that the observed metabolic reprogramming may result from both decreased folate availability and altered folate metabolism. These findings reveal that folate restriction results in metabolic and bioenergetic changes and a less aggressive cancer cell phenotype.
  
  
  
  Metabolic reprogramming driven by folate restriction represents a therapeutic target for reducing the burden of breast cancer. Mol Cancer Res; 15(2); 189-200. ©2016 AACR.
authors.affiliation: Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Ashkavand
authors.affiliation: The Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Ciara
authors.initials: C
authors.lastname: O'Flanagan
authors.affiliation: Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina.|The Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Mirko
authors.initials: M
authors.lastname: Hennig
authors.affiliation: The Department of Bioinformatics & Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina.
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Du
authors.affiliation: Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina.|The Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.affiliation: Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina. sergey_krupenko@unc.edu.|The Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Krupenko
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D065150:Cellular Reprogramming; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D015398:Signal Transduction
chemical_list: D005492:Folic Acid