Inhibition of NFκB induces caspase-independent cell death in human T lymphocytes

Nuclear factor κB (NFκB) regulates the expression of various genes essential for cell survival. Here we demonstrate that suppression of NFκB nuclear import with SN50 peptide carrying the nuclear localization sequence (NLS) of the NFκB p50 subunit induces apoptosis in human peripheral blood T lymphocytes (T-PBL), which can be blocked with the pan-caspase inhibitor Z-VAD.fmk. However, even when caspase function is blocked, the addition of SN50 induces irreversible cell loss due to the reduction in the mitochondrial transmembrane potential (Δψm) followed by disruption of the cell membrane, hallmarks of necrosis. These observations demonstrate that although inhibition of NFκB nuclear translocation by SN50 peptide can induce caspase-dependent apoptosis in T-PBL, cell death may still proceed in the absence of functional caspase activity. The availability of downstream caspases appears to determine the mode of cell death in NFκB defective cells.