title: Toxin-induced increase in survival factor receptors: modulation of the threshold for apoptosis.
abstract: The threshold at which toxins induce cell death is thought to directly relate to the amount of injury sustained. We show that the threshold at which a cell initiates toxin-induced death may vary in response to changes in the trophic environment. Treatment of Rat-1 fibroblasts with 50-175 mM dimethylformamide (DMF) induced cell death by apoptosis. Addition of insulin-like growth factor 1 (IGF-1; 100 ng/ml) and/or overexpression of the IGF-1 receptor (IGF-1R) attenuated the cytotoxicity of DMF. Furthermore, 95-99% of cells were protected from DMF-induced apoptosis if cells were pretreated with platelet-derived growth factor (5 ng/ml) for 16 h before treatment with DMF in the presence of IGF-1. Platelet-derived growth factor induced the expression of IGF-1R mRNA. The ability of cells to proliferate and survive after a 24-h treatment with DMF was determined by colony formation; whereas treatment with concentrations of >130 mM DMF reduced cellular survival, exposure to concentrations of <130 mM unexpectedly increased the colony-forming ability of treated cells when compared to that of controls. Treatment of Rat-1 fibroblasts with 75 and 130 mM DMF induced IGF-1R mRNA as determined by reverse transcription-PCR analysis. Serum withdrawal also transiently increased the expression of IGF-1R mRNA in Rat-1 fibroblasts. These results show that cells can actively adapt to pathological and physiological stress by up-regulating receptors that provide signals for cellular survival. We suggest that the threshold for toxin-induced apoptosis is determined not only by the extent of cytotoxic damage but also by the trophic environment and the ability of a cell to modulate survival signals that attenuate toxicity.
authors.affiliation: School of Biological Sciences, University of Manchester, United Kingdom.
authors.forename: C C
authors.initials: CC
authors.lastname: Boyle
authors.forename: J A
authors.initials: JA
authors.lastname: Hickman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D004126:Dimethylformamide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008854:Microscopy, Electron; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D004126:Dimethylformamide