TNF treatment causes oxidative down-modulation of endogenous survival factors in transformed as well as nontransformed fibroblasts. Endogenous survival factors are negative regulators of a constitutively expressed apoptosis machinery and have been defined in several cellular systems. As transformed cells harbour lower concentrations of endogenous survival factors than nontransformed parental cells, TNF-dependent down-modulation of endogenous survival factors in transformed cells is sufficient to release the apoptosis machinery from negative control and to cause cell death. In contrast, in nontransformed cells, due to their higher initial concentration of endogenous survival factors, down-modulation by TNF is not complete and therefore apoptosis is still prevented. Our data showed that perception of TNF signalling is not different between transformed and nontransformed cells, but that their differential response is due to quantitative differences in their regulatory setup. Furthermore, our data explained why application of low concentrations of cycloheximide can sensitize cells for apoptosis induction by TNF-alpha.
