The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphornas

The NF-kappa B pathways have been implicated in tumorigenesis in several lymphoid malignancies, including non-Hodgkin's and Hodgkin's lymphomas. However, the antiapoptotic functions and the mechanism responsible for signaling through each NF-kappa B pathway remain to be elucidated. In the current study, lymphoma cell lines with constitutively active NF-kappa B were found to be resistant to inducers of the extrinsic and intrinsic apoptosis pathways. Resistance to cell death resulted from blocks early and late in the apoptosis cascade. Several NF-kappa B target genes were overexpressed in these cell lines, including Bcl-xL, Fas-associated death domain-like IL-1 beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. Inhibition of the canonical or noncanonical NF-kappa B pathways with small interfering RNAs or adenovirus expressing a stable form of inhibitor of NF-kappa B (I kappa B) enhanced sensitivity to apoptosis inducers and resulted in lower levels of Bcl-xL or Fas-associated death domain-like IL-1 beta-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. These findings demonstrate an important role of both NF-kappa B pathways in mediating resistance to apoptosis and distinctive antiapoptotic downstream target gene profiles responsible for this effect.