Inhibition of Nuclear Factor κB Activation Attenuates Apoptosis Resistance in Lymphoid Cells

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Abstract
Death-inducing ligands (DILs) such as tumor necrosis factor α (TNFα) or the cytotoxic drug doxorubicin have been shown to activate a nuclear factor κB (NFκB)-dependent program that may rescue cells from apoptosis induction. We demonstrate here that TRAIL (TNF-related apoptosis-inducing ligand), a recently identified DIL, also activates NFκB in lymphoid cell lines in a kinetic similar to TNFα. NFκB activity is independent from FADD, caspases, and apoptosis induction. To study the influence of NFκB activity on apoptosis mediated by TRAIL, CD95, TNFα, or doxorubicin, NFκB activation was inhibited using the proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal or transient overexpression of mutant IκBα. Sensitivity for induction of apoptosis was markedly increased by these treatments in apoptosis sensitive cell lines. Moreover, both in cell lines and in primary leukemia cells that are resistant towards induction of apoptosis by DILs and doxorubicin, antagonization of NFκB activity partially restored apoptosis sensitivity. These data suggest that inhibition of NFκB activation may provide a molecular approach to increase apoptosis sensitivity in anticancer treatment.