The pro- or anti-apoptotic function of NF-kappa B is determined by the nature of the apoptotic stimulus

To test whether the behaviour of transcription factor NF-kappa B as a promo ter or antagonist of apoptosis depends on the apoptotic stimulus, we determ ined the influence of NF-kappa B on cell killing elicited by a variety of i nducers within a given cell type. Inhibition of NF-kappa B by genetic and p harmacological approaches rendered HeLa cells more susceptible to TNF-alpha -induced cell killing, but protected them almost completely from H2O2- and pervanadate-induced apoptosis. TNF-alpha was unable to protect HeLa from H2 O2- and pervanadate-induced apoptosis and further enhanced the cytotoxicity induced by these two adverse agents. Supernatants from HeLa cells stably o verexpressing a transdominant negative form of I kappa B-alpha selectively increased the cytotoxicity of TNF-alpha for HeLa cells, suggesting that the enhanced susceptibility of these cells can be attributed to one or more se cretable factors. Supershift experiments showed that the various apoptotic stimuli induced the same subset of DNA-binding subunits. Therefore, the nat ure of the signals elicited by the respective death inducers determines whe ther NF-kappa B induction leads to apoptosis or survival, suggesting that t he manipulation of NF-kappa B activity may provide a new approach to adjuva nt therapy in cancer treatment.