In diverse cell types, NF-kappa B transcription factors have been shown to have a role in regulating the apoptotic program, either as essential for the induction of apoptosis or, perhaps more commonly, as blockers of apoptosis, We investigated the role of NF-kappa B activation in the TNF-alpha-mediated apoptosis in lung cancer cells. TNF-alpha-resistant NCI-H157 cells became sensitized to TNF-alpha by prior treatment with cycloheximide, suggesting the presence of newly synthesized anti-apoptotic protein(s). We next evaluated whether the transcription of antiapoptotic protein(s) depends on the activation of NF-kappa B. NF-kappa B activation was blocked by either adenovirus-mediated overexpression of I kappa B alpha superrepressor or pretreatment with proteasome inhibitor, MG132. Both methods of blocking NF-kappa B activation enhanced TNF-alpha-induced apoptosis in NCI-H157 cells. These results suggest that NF-kappa B activation confers resistance to TNF-alpha-mediated apoptosis in lung cancer cells.