title: Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas.
abstract: BACKGROUND
  Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial. Thus, we aimed to understand the role of hypoxia in the regulation of MCT expression and function in GBM, MCT1 in particular.
  
  
  METHODS
  Expression of hypoxia- and glycolytic-related markers, as well as MCT1 and MCT4 isoforms was assessed in in vitro and in vivo orthotopic glioma models, and also in human GBM tissues by immunofluorescence/immunohistochemistry and Western blot. Following MCT1 inhibition, either pharmacologically with CHC (α-cyano-4-hydroxynnamic acid) or genetically with siRNAs, we assessed GBM cell viability, proliferation, metabolism, migration and invasion, under normoxia and hypoxia conditions.
  
  
  RESULTS
  Hypoxia induced an increase in MCT1 plasma membrane expression in glioma cells, both in in vitro and in vivo models. Additionally, treatment with CHC and downregulation of MCT1 in glioma cells decreased lactate production, cell proliferation and invasion under hypoxia. Moreover, in the in vivo orthotopic model and in human GBM tissues, there was extensive co-expression of MCT1, but not MCT4, with the GBM hypoxia marker CAIX.
  
  
  CONCLUSIONS
  Hypoxia-induced MCT1 supports GBM glycolytic phenotype, being responsible for lactate efflux and an important mediator of cell survival and aggressiveness. Therefore, MCT1 constitutes a promising therapeutic target in GBM.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Vera
authors.initials: V
authors.lastname: Miranda-Gonçalves
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Granja
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.|Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
authors.forename: Olga
authors.initials: O
authors.lastname: Martinho
authors.affiliation: Department of Pathology, Hospital Pedro Hispano, Matosinhos, Portugal.
authors.forename: Mrinalini
authors.initials: M
authors.lastname: Honavar
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Pojo
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Costa
authors.affiliation: Unit of Neuropathology, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Manuel M
authors.initials: MM
authors.lastname: Pires
authors.affiliation: Department of Neurosurgery, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Pinheiro
authors.affiliation: Hospital Dr. Nélio Mendonça, Funchal, Madeira, Portugal.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cordeiro
authors.affiliation: Hospital Dr. Nélio Mendonça, Funchal, Madeira, Portugal.
authors.forename: Gil
authors.initials: G
authors.lastname: Bebiano
authors.affiliation: Radiotherapy Service, Centro Hospitalar do Montijo, Setúbal, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Costa
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.|Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
authors.forename: Rui M
authors.initials: RM
authors.lastname: Reis
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Baltazar
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006019:Glycolysis / Q000502:physiology; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis*; D010641:Phenotype; D027981:Symporters / Q000096:biosynthesis*; D015854:Up-Regulation; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1
keywords: Warburg effect; glioblastomas; lactate; monocarboxylate transporters (MCTs); tumor hypoxia