title: Glyoxalase I inhibition induces apoptosis in irradiated MCF-7 cells via a novel mechanism involving Hsp27, p53 and NF-κB.
abstract: BACKGROUND
  Glyoxalase I (GI) is a cellular defence enzyme involved in the detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis, and MG-derived advanced glycation end products (AGEs). Argpyrimidine (AP), one of the major AGEs coming from MG modifications of proteins arginines, is a pro-apoptotic agent. Radiotherapy is an important modality widely used in cancer treatment. Exposure of cells to ionising radiation (IR) results in a number of complex biological responses, including apoptosis. The present study was aimed at investigating whether, and through which mechanism, GI was involved in IR-induced apoptosis.
  
  
  METHODS
  Apoptosis, by TUNEL assay, transcript and protein levels or enzymatic activity, by RT-PCR, western blot and spectrophotometric methods, respectively, were evaluated in irradiated MCF-7 breast cancer cells, also in experiments with appropriate inhibitors or using small interfering RNA.
  
  
  RESULTS
  Ionising radiation induced a dramatic reactive oxygen species (ROS)-mediated inhibition of GI, leading to AP-modified Hsp27 protein accumulation that, in a mechanism involving p53 and NF-κB, triggered an apoptotic mitochondrial pathway. Inhibition of GI occurred at both functional and transcriptional levels, the latter occurring via ERK1/2 MAPK and ERα modulation.
  
  
  CONCLUSIONS
  Glyoxalase I is involved in the IR-induced MCF-7 cell mitochondrial apoptotic pathway via a novel mechanism involving Hsp27, p53 and NF-κB.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Sant'Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Antognelli
authors.affiliation: Radiation Oncology Section, University of Perugia, Sant'Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Palumbo
authors.affiliation: Radiation Oncology Section, University of Perugia, Sant'Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Aristei
authors.affiliation: Department of Experimental Medicine, University of Perugia, Sant'Andrea delle Fratte, 06132 Perugia, Italy.
authors.forename: V N
authors.initials: VN
authors.lastname: Talesa
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy; D018929:Cell Culture Techniques; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D018832:Molecular Chaperones; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000528:radiation effects; D034741:RNA, Small Interfering / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007791:Lactoylglutathione Lyase