Propapoptotic effects of NF-κB in LNCaP prostate cancer cells lead to serine protease activation

LNCaP prostate cancer cells are resistant to induction of apoptosis by γ-irradiation and partially sensitive to TNF-α or FAS antibody, irradiation sensitizes cells to apoptosis induced by FAS antibody or TNF-α. LNCaP cell clones stably expressing IκBα super repressor were resistant to apoptosis induced by death ligands in the presence or absence of irradiation. IκBα super repressor expression also increased clonogenic survival after exposure to TNF-α+irradiation, but had no effect on survival after irradiation alone. IκBα super repressor expression blocked the increase of whole cell and cell surface FAS expression induced by TNF-α, but did not effect induction of FAS expression and cell surface FAS expression that resulted from irradiation. In cells expressing IκBα super repressor there was diminished activation of caspases-8 and -7 and diminished production of proscas-pases-8 and -7, usually required for death induction in LNCaP cells. Peptide inhibitors of caspase activation complemented the IκBα super repressor inhibition of apoptosis, but peptide inhibitors of serine proteases had no effect on LNCaP cells expressing IκBα super repressor. Moreover, cleavage of a serine protease substrate was induced by treatment of LNCaP cells with TNF-α and irradiation. The data suggest that in LNCaP cells NF-κB mediates a proapoptotic pathway that leads to activation of proapoptotic serine proteases.