Modulation of the Threshold for Apoptosis Toxin-induced Increase in Survival Factor Receptors: Updated Version

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-i fibroblasts with 50—175 mM dimethylformamide (DMF) induced cell death by apoptosis. Addition of insulin-like growth factor 1 (IGF-i; 100 ng/ml) and/or overexpression of the IGF-i receptor (IGF-iR) attenuated the cytotoxicity of DMF. Furthermore, 95—99% of cells were protected from DMF-induced apop tosis if cells were pretreated with platelet-derived growth factor (5 ag/mI) 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 concentra lions of > 130 mM DMF reduced cellular survival, exposure to concentra tions of < 130 mM unexpectedly increased the colony-forming ability of treated cells when compared to that of controls. Treatment of Rat-i fibroblasts with 75 and 130 mii DMF induced IGF-iR mRNA as deter mined by reverse transcription-PCR analysis. Serum withdrawal also transiently increased the expression of IGF-iR mRNA in Rat-i ftbro blasts. 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 apop tosis 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.