title: The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil.
abstract: BACKGROUND
  Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H+-ATPase (β-F1-ATPase). The bioenergetic signature is a protein ratio (β-F1-ATPase/GAPDH), which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a viable alternative to conventional anticancer chemotherapies. Herein, we document that the bioenergetic signature of isogenic colon cancer cells provides a gauge to predict the cell-death response to the metabolic inhibitors, 3-bromopyruvate (3BrP) and iodoacetate (IA), and the anti-metabolite, 5-fluorouracil (5-FU).
  
  
  METHODS
  The bioenergetic signature of the cells was determined by western blotting. Aerobic glycolysis was determined from lactate production rates. The cell death was analyzed by fluorescence microscopy and flow cytometry. Cellular ATP concentrations were determined using bioluminiscence. Pearson's correlation coefficient was applied to assess the relationship between the bioenergetic signature and the cell death response. In vivo tumor regression activities of the compounds were assessed using a xenograft mouse model injected with the highly glycolytic HCT116 colocarcinoma cells.
  
  
  RESULTS
  We demonstrate that the bioenergetic signature of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the bioenergetic signature directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the in vitro cell-death responses associated with 3BrP, IA and 5-FU, the in vivo tumor regression activities of these agents were comparable.
  
  
  CONCLUSIONS
  Overall, we suggest that the determination of the bioenergetic signature of colon carcinomas could provide a tool for predicting the therapeutic response to various chemotherapeutic strategies aimed at combating tumor progression.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Raras CIBERER-ISCIII, Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Sánchez-Aragó
authors.forename: José M
authors.initials: JM
authors.lastname: Cuezva
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004734:Energy Metabolism / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology*; D005973:Glutamine / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D007461:Iodoacetates / Q000494:pharmacology*; D011773:Pyruvates / Q000494:pharmacology*; D012074:Remission Induction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007461:Iodoacetates; D011773:Pyruvates; D005973:Glutamine; C017092:bromopyruvate; D000255:Adenosine Triphosphate; D005472:Fluorouracil