Inhibition of NF-kappaB activity enhances TRAIL mediated apoptosis in breast cancer cell lines.
Most breast cancer cell lines are resistant to TNF-related apoptosis inducing ligand (TRAIL) induced apoptosis. In sensitive breast cancer cell lines TRAIL rapidly induces the cleavage and activation of caspases leading to the subsequent cleavage of downstream caspase substrates. In contrast, there is no caspase activation in the resistant cell lines. The transcription factor NF-KB can inhibit apoptosis induced by a variety of stimuli including activation of death receptors. We investigated whether NF-kappaB contributes to the resistance of breast cancer cells to TRAIL induced apoptosis. All of the resistant breast cancer cell lines expressed NF-kappaB and had detectable NF-kappaB activity in nuclear extracts prior to treatment with TRAIL. 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 contributes to the resistance of these cell lines to TRAIL, we transiently transfected the resistant cell lines with an inhibitor of NF-kappaB (IkappaBdeltaN) and measured TRAIL induced apoptosis in control and transfected cells. All of the resistant cell lines tested showed an increase in TRAIL induced apoptosis when transfected with the IKBdeltaN. These results demonstrate that TRAIL resistant breast cancer cells fail to rapidly activate the apoptotic machinery but they do activate NF-kappaB. Inhibition of NF-kappaB activity increases the sensitivity to TRAIL mediated apoptosis in resistant cells. These results suggest that agents which inhibit NF-kappaB should increase the clinical efficacy of TRAIL in breast cancer cells.
Keane
M M
MM
Genetics Department, Medicine Branch, National Cancer Institute, Bethesda 20889, MD, USA.
Rubinstein
Y
Y
Cuello
M
M
Ettenberg
S A
SA
Banerjee
P
P
Nau
M M
MM
Lipkowitz
S
S
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000473:pathology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D016328:NF-kappa B / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha