Inhibition of NF-kappa B activity enhances TRAIL mediated apoptosis in breast cancer cell lines

Most breast cancer cell lines are resistant to TNF-related apoptosis induci ng ligand (TRAIL) induced apoptosis. In sensitive breast cancer cell lines TRAIL rapidly induces the cleavage and activation of caspases leading to th e subsequent cleavage of downstream caspase substrates. In contrast, there is no caspase activation in the resistant cell lines. The transcription fac tor NF-kappaB can inhibit apoptosis induced by a variety of stimuli includi ng activation of death receptors. We investigated whether NF-kappaB contrib utes to the resistance of breast cancer cells to TRAIL induced apoptosis. A ll of the resistant breast cancer cell lines expressed NF-kappaB and had de tectable NF-kappaB activity in nuclear extracts prior to treatment with TRA IL. Upon TRAIL treatment, a significant increase in NF-kappaB activity was seen in most of the cell lines. To directly test if NF-kappaB activity cont ributes to the resistance of these cell lines to TRAIL, we transiently tran sfected the resistant cell lines with an inhibitor of NF-kappaB (I kappaB D eltaN) and measured TRAIL induced apoptosis in control and transfected cell s. All of the resistant cell lines tested showed an increase in TRAIL induc ed apoptosis when transfected with the I kappaB DeltaN. These results demon strate that TRAIL resistant breast cancer cells fail to rapidly activate th e apoptotic machinery but they do activate NF-kappaB. Inhibition of NF-kapp aB activity increases the sensitivity to TRAIL mediated apoptosis in resist ant cells. These results suggest that agents which inhibit NF-kappaB should increase the clinical efficacy of TRAIL in breast cancer cells.