title: TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown results in radiosensitization of glioma cells.
abstract: OBJECTIVE
  The TP53 induced glycolysis and apoptosis regulator (TIGAR) functions to lower fructose-2,6-bisphosphate (Fru-2,6-P(2)) levels in cells, consequently decreasing glycolysis and leading to the scavenging of reactive oxygen species (ROS), which correlate with a higher resistance to cell death. The decrease in intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic lesions. Given these good prospects of TIGAR for metabolic regulation and p53-response modulation, we analyzed the effects of TIGAR knockdown in U87MG and T98G glioblastoma-derived cell lines.
  
  
  RESULTS
  After TIGAR-knockdown in glioblastoma cell lines, different metabolic parameters were assayed, showing an increase in Fru-2,6-P(2), lactate and ROS levels, with a concomitant decrease in reduced glutathione (GSH) levels. In addition, cell growth was inhibited without evidence of apoptotic or autophagic cell death. In contrast, a clear senescent phenotype was observed. We also found that TIGAR protein levels were increased shortly after irradiation. In addition, avoiding radiotherapy-triggered TIGAR induction by gene silencing resulted in the loss of capacity of glioblastoma cells to form colonies in culture and the delay of DNA repair mechanisms, based in γ-H2AX foci, leading cells to undergo morphological changes compatible with a senescent phenotype. Thus, the results obtained raised the possibility to consider TIGAR as a therapeutic target to increase radiotherapy effects.
  
  
  CONCLUSIONS
  TIGAR abrogation provides a novel adjunctive therapeutic strategy against glial tumors by increasing radiation-induced cell impairment, thus allowing the use of lower radiotherapeutic doses.
authors.affiliation: Unitat de Bioquímica, Campus de Ciències de la Salut, Institut d’Investigació Biomèdica de Bellvitge-Universitat de Barcelona, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Peña-Rico
authors.forename: María Nieves
authors.initials: MN
authors.lastname: Calvo-Vidal
authors.forename: Ruth
authors.initials: R
authors.lastname: Villalonga-Planells
authors.forename: Fina
authors.initials: F
authors.lastname: Martínez-Soler
authors.forename: Pepita
authors.initials: P
authors.lastname: Giménez-Bonafé
authors.forename: Àurea
authors.initials: À
authors.lastname: Navarro-Sabaté
authors.forename: Avelina
authors.initials: A
authors.lastname: Tortosa
authors.forename: Ramon
authors.initials: R
authors.lastname: Bartrons
authors.forename: Anna
authors.initials: A
authors.lastname: Manzano
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015153:Blotting, Western; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000473:pathology / Q000532:radiotherapy*; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C525108:apoptosis-induced regulator protein; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human