title: Energy metabolism in H460 lung cancer cells: effects of histone deacetylase inhibitors.
abstract: BACKGROUND
  Tumor cells are characterized by accelerated growth usually accompanied by up-regulated pathways that ultimately increase the rate of ATP production. These cells can suffer metabolic reprogramming, resulting in distinct bioenergetic phenotypes, generally enhancing glycolysis channeled to lactate production. In the present work we showed metabolic reprogramming by means of inhibitors of histone deacetylase (HDACis), sodium butyrate and trichostatin. This treatment was able to shift energy metabolism by activating mitochondrial systems such as the respiratory chain and oxidative phosphorylation that were largely repressed in the untreated controls.
  
  
  RESULTS
  Various cellular and biochemical parameters were evaluated in lung cancer H460 cells treated with the histone deacetylase inhibitors (HDACis), sodium butyrate (NaB) and trichostatin A (TSA). NaB and TSA reduced glycolytic flux, assayed by lactate release by H460 cells in a concentration dependent manner. NaB inhibited the expression of glucose transporter type 1 (GLUT 1), but substantially increased mitochondria bound hexokinase (HK) activity. NaB induced increase in HK activity was associated to isoform HK I and was accompanied by 1.5 fold increase in HK I mRNA expression and cognate protein biosynthesis. Lactate dehydrogenase (LDH) and pyruvate kinase (PYK) activities were unchanged by HDACis suggesting that the increase in the HK activity was not coupled to glycolytic flux. High resolution respirometry of H460 cells revealed NaB-dependent increased rates of oxygen consumption coupled to ATP synthesis. Metabolomic analysis showed that NaB altered the glycolytic metabolite profile of intact H460 cells. Concomitantly we detected an activation of the pentose phosphate pathway (PPP). The high O(2) consumption in NaB-treated cells was shown to be unrelated to mitochondrial biogenesis since citrate synthase (CS) activity and the amount of mitochondrial DNA remained unchanged.
  
  
  CONCLUSIONS
  NaB and TSA induced an increase in mitochondrial function and oxidative metabolism in H460 lung tumor cells concomitant with a less proliferative cellular phenotype.
authors.affiliation: Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, Brazil.
authors.forename: Nívea Dias
authors.initials: ND
authors.lastname: Amoêdo
authors.forename: Mariana Figueiredo
authors.initials: MF
authors.lastname: Rodrigues
authors.forename: Paula
authors.initials: P
authors.lastname: Pezzuto
authors.forename: Antonio
authors.initials: A
authors.lastname: Galina
authors.forename: Rodrigo Madeiro
authors.initials: RM
authors.lastname: da Costa
authors.forename: Fábio Ceneviva Lacerda
authors.initials: FC
authors.lastname: de Almeida
authors.forename: Tatiana
authors.initials: T
authors.lastname: El-Bacha
authors.forename: Franklin David
authors.initials: FD
authors.lastname: Rumjanek
mesh_terms: D002087:Butyrates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D042843:Glucose 1-Dehydrogenase / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011770:Pyruvate Kinase / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D002087:Butyrates; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007773:Lactates; C495677:SLC2A1 protein, human; C495687:SLC2A3 protein, human; C012589:trichostatin A; D007770:L-Lactate Dehydrogenase; D042843:Glucose 1-Dehydrogenase; D013385:Succinate Dehydrogenase; D006593:Hexokinase; D011770:Pyruvate Kinase