title: Oxidative stress and glyoxalase I activity mediate dicarbonyl toxicity in MCF-7 mamma carcinoma cells and a tamoxifen resistant derivative.
abstract: BACKGROUND
  Acquired tamoxifen resistance is a significant problem in estrogen receptor positive breast cancer. In a cellular model, tamoxifen resistance was associated with increased sensitivity towards toxic dicarbonyls and reduced free sulfhydryl group content. We here analyzed the role of oxidative stress and glyoxalase I activity on dicarbonyl resistance and the significance of glyoxalase I expression for survival.
  
  
  METHODS
  Reactive oxygen species were determined by 2,7-dihydrochlorofluorescein diacetate. Inhibitors for NADPH-oxidase (diphenyleneiodonium), p38 MAPK (SB203580) and ERK1/2 (UO126) were applied to investigate interactions of these signaling molecules. N-acetyl cysteine was used to evaluate the effect of oxidative stress on cell viability, which was assessed by the resazurin assay. Gene expression was analyzed by real time qRT-PCR. Glyoxalase activity was inhibited by the specific inhibitor CS-0683 and siRNA. The relevance of glyoxalase 1 mRNA abundance on survival of breast cancer patients was evaluated by the KM-plotter web interface.
  
  
  RESULTS
  α-Oxo-aldehydes caused an immediate increase in reactive oxygen species where the tamoxifen resistant cell line (TamR) responded at lower concentrations than the MCF-7 parental cell line. Inhibitor studies placed ROS production by NADPH-oxidase downstream of p38 MAPK. The antioxidant N-acetyl cysteine (NAC) increased survival, whereas glyoxalase (GLO1) inhibition increased dicarbonyl toxicity. GLO1 mRNA abundance was correlated with unfavorable prognosis of breast cancer patients.
  
  
  CONCLUSIONS
  Dicarbonyl toxicity was mediated by oxidative stress and GLO1 activity determines aldehyde toxicity in tamoxifen resistant cells.
  
  
  CONCLUSIONS
  Glyoxalases might be predictive biomarkers for tamoxifen resistance and a putative target for the treatment of tamoxifen resistant breast cancer patients.
authors.affiliation: Otto von Guericke University Magdeburg, Department of Pathology, Leipziger Str. 44, House 28, D-39120 Magdeburg, Germany. Electronic address: norbert.nass@med.ovgu.de.
authors.forename: Norbert
authors.initials: N
authors.lastname: Nass
authors.affiliation: University of Heidelberg, Department of Ophthalmology, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany.
authors.forename: Saadettin
authors.initials: S
authors.lastname: Sel
authors.affiliation: Otto von Guericke University Magdeburg, Department of Obstetrics and Gynecology, Gerhart-Hauptmann Str. 35, 39108 Magdeburg, Germany.
authors.forename: Atanas
authors.initials: A
authors.lastname: Ignatov
authors.affiliation: Otto von Guericke University Magdeburg, Department of Pathology, Leipziger Str. 44, House 28, D-39120 Magdeburg, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
authors.affiliation: Otto von Guericke University Magdeburg, Department of Pathology, Leipziger Str. 44, House 28, D-39120 Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kalinski
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000447:Aldehydes / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000502:physiology*; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D000447:Aldehydes; D017382:Reactive Oxygen Species; D013629:Tamoxifen; D007791:Lactoylglutathione Lyase; D000111:Acetylcysteine
keywords: Glyoxal; Glyoxalase; MAP-kinase signaling; Methylglyoxal; NF-κB; Protein kinase B (AKT); Reactive oxygen species (ROS)