title: Overexpression of pyruvate dehydrogenase kinase supports dichloroacetate as a candidate for cutaneous melanoma therapy.
abstract: OBJECTIVE
  We aimed to verify if there is evidence to consider dichloroacetate (DCA), which inhibits the pyruvate dehydrogenase kinase (PDK) and reverts the metabolic shift of cancer cells from glycolysis to oxidative phosphorylation, as a promising drug for therapy of cutaneous melanoma (CM) patients.
  
  
  METHODS
  We assessed the expression profile of PDK 1, 2 and 3 in a series of melanoma samples, to verify if melanoma tumors express the DCA targets, if this expression correlates with the activation of important signaling cascades for melanomagenesis and also with the prognosis of melanoma patients. We also established the sensitivity of melanoma cell lines to DCA treatment, by assessing their metabolic alterations, proliferation and survival.
  
  
  RESULTS
  We observed that both PDK 1 and 2 isoforms are overexpressed in CM compared to nevi, this expression being associated with the expression of the mTOR pathway effectors and independent of the BRAF mutational status. Melanoma cell lines treated with DCA showed a shift in metabolism, that is, a decrease in glucose consumption and lactate production, downregulation of proliferation, an increase of apoptosis and a decrease in mTOR pathway activation.
  
  
  CONCLUSIONS
  Our results suggest that PDK expression may play a role in melanoma development and that DCA can be useful for CM therapy, alone or in combination with mTOR inhibitors.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), University of Porto , Porto , Portugal +22 557 0700 ; +22 557 0799 ; psoares@ipatimup.pt.
authors.forename: Helena
authors.initials: H
authors.lastname: Pópulo
authors.forename: Regina
authors.initials: R
authors.lastname: Caldas
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lopes
authors.forename: Joana
authors.initials: J
authors.lastname: Pardal
authors.forename: Valdemar
authors.initials: V
authors.lastname: Máximo
authors.forename: Paula
authors.initials: P
authors.lastname: Soares
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology; D008875:Middle Aged; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D013534:Survival; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases
keywords: dichloroacetate; mTOR; melanoma; metabolism; pyruvate dehydrogenase kinase