The activation of the transcription factor nuclear factor-kappa B (NF-κB) by tumor necrosis factor (TNF), ionizing radiation, or daunorubicin (a cancer chemotherapeutic compound) protects cells from apoptosis. Inhibition of NF-κB nuclear translocation enhances apoptotic killing by these reagents but not by apoptotic stimuli that do not activate NF-κB. This suggests that NF-κB plays a protective role against apoptotic cell death induced by certain stimuli. The study used the human fibrosarcoma cell line HT1080, which is resistant to TNF-induced apoptosis, and established a super-repressor form of the NF-κB inhibitor IκBα to block NF-κB activation. Overexpression of this super-repressor in HT1080 cells significantly enhanced TNF-induced apoptosis. Similar results were observed with other apoptotic stimuli such as ionizing radiation and daunorubicin, but not with staurosporine. The activation of NF-κB by these stimuli provides protection against apoptosis, and inhibiting NF-κB function may improve the efficacy of cancer therapies.The activation of the transcription factor nuclear factor-kappa B (NF-κB) by tumor necrosis factor (TNF), ionizing radiation, or daunorubicin (a cancer chemotherapeutic compound) protects cells from apoptosis. Inhibition of NF-κB nuclear translocation enhances apoptotic killing by these reagents but not by apoptotic stimuli that do not activate NF-κB. This suggests that NF-κB plays a protective role against apoptotic cell death induced by certain stimuli. The study used the human fibrosarcoma cell line HT1080, which is resistant to TNF-induced apoptosis, and established a super-repressor form of the NF-κB inhibitor IκBα to block NF-κB activation. Overexpression of this super-repressor in HT1080 cells significantly enhanced TNF-induced apoptosis. Similar results were observed with other apoptotic stimuli such as ionizing radiation and daunorubicin, but not with staurosporine. The activation of NF-κB by these stimuli provides protection against apoptosis, and inhibiting NF-κB function may improve the efficacy of cancer therapies.