title: Induction of transcription factor CEBP homology protein mediates hypoglycaemia-induced necrotic cell death in human neuroblastoma cells.
abstract: Oxygen and glucose deprivation are direct consequences of tissue ischaemia. We explored the interaction of hypoxia and hypoglycaemia on cell survival and gene expression in the absence of glutamatergic signalling using human SH-SY5Y neuroblastoma cells as a model. In agreement with previous investigations in non-neural cells, prolonged hypoxia (0.5% O(2)) failed to induce significant cell death in this system. In contrast, exposure to hypoglycaemia induced significant necrotic cell death (> 80% after 72 h). Interestingly, hypoglycaemia-induced cell death was completely abrogated by simultaneous exposure to hypoxia, suggesting strong cytoprotective effects of hypoxia. Subsequent microarray analysis of the underlying transcriptional responses revealed that the transcription factor CEBP homology protein (CHOP) was strongly induced by hypoglycaemia, and suppressed by simultaneous hypoxia. RNA interference against CHOP significantly protected cells from glucose deprivation-induced cell death. Hypoxia-induced vascular endothelial growth factor (VEGF) activation also protected cells against hypoglycaemia-induced cell death, but VEGF failed to modify hypoglycaemia-induced CHOP induction. Our data suggest that hypoglycaemia-induced necrotic cell death of neuroblastoma cells is an active process mediated via the induction of the transcription factor CHOP, and that hypoxia counteracts this cell death via at least two distinct mechanisms: repression of CHOP and induction of VEGF.
authors.affiliation: Experimental Neurosurgery, Center for Neurology and Neurosurgery, Johann Wolfgang Goethe University Clinics, Frankfurt, Germany.
authors.forename: Donat
authors.initials: D
authors.lastname: Kögel
authors.forename: Birte
authors.initials: B
authors.lastname: Svensson
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Copanaki
authors.forename: Sergio
authors.initials: S
authors.lastname: Anguissola
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonner
authors.forename: Nadia
authors.initials: N
authors.lastname: Thurow
authors.forename: Daniel
authors.initials: D
authors.lastname: Gudorf
authors.forename: Holger
authors.initials: H
authors.lastname: Hetschko
authors.forename: Thorsten
authors.initials: T
authors.lastname: Müller
authors.forename: Marion
authors.initials: M
authors.lastname: Peters
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: König
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D005456:Fluorescent Dyes; D005947:Glucose / Q000172:deficiency; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism*; D000860:Hypoxia / Q000473:pathology; D009336:Necrosis; D009447:Neuroblastoma / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D005456:Fluorescent Dyes; D042461:Vascular Endothelial Growth Factor A; D053148:Caspase 3; D005947:Glucose