Toxin-induced increase in survival factor receptors: modulation of the threshold for apoptosis.
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.
Boyle
C C
CC
School of Biological Sciences, University of Manchester, United Kingdom.
Hickman
J A
JA
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
D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D004126:Dimethylformamide