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Inhibition of nuclear factor kappaB activation attenuates apoptosis resistance in lymphoid cells
I Jeremias1, C Kupatt, B Baumann
1Division of Molecular Oncology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Abstract:
Death-inducing ligands (DILs) such as tumor necrosis factor alpha (TNFalpha) or the cytotoxic drug doxorubicin have been shown to activate a nuclear factor kappaB (NFkappaB)-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 NFkappaB in lymphoid cell lines in a kinetic similar to TNFalpha. NFkappaB activity is independent from FADD, caspases, and apoptosis induction. To study the influence of NFkappaB activity on apoptosis mediated by TRAIL, CD95, TNFalpha, or doxorubicin, NFkappaB activation was inhibited using the proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal or transient overexpression of mutant IkappaBalpha. 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 NFkappaB activity partially restored apoptosis sensitivity. These data suggest that inhibition of NFkappaB activation may provide a molecular approach to increase apoptosis sensitivity in anticancer treatment.
Insights
Inhibiting nuclear factor kappaB (NFkappaB) activation enhances cancer cell sensitivity to apoptosis induced by death-inducing ligands and doxorubicin. This suggests NFkappaB inhibition as a potential anticancer treatment strategy.
Area of Science:
- Molecular Biology
- Cell Biology
- Immunology
Background:
- Death-inducing ligands (DILs) and cytotoxic drugs can trigger cell death pathways.
- Nuclear factor kappaB (NFkappaB) activation is a cellular response that can promote cell survival.
- The role of NFkappaB in modulating sensitivity to apoptosis induced by various death signals requires further elucidation.
Purpose of the Study:
- To investigate the activation kinetics of NFkappaB by TRAIL (TNF-related apoptosis-inducing ligand) and its relationship with apoptosis.
- To determine the effect of NFkappaB inhibition on apoptosis sensitivity induced by DILs and doxorubicin.
- To explore the potential of targeting NFkappaB for enhancing anticancer therapies.
Main Methods:
- Assessing NFkappaB activation in lymphoid cell lines upon stimulation with TRAIL and TNFalpha.
- Inhibiting NFkappaB using the proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal or IkappaBalpha mutants.
- Evaluating apoptosis induction in cancer cell lines and primary leukemia cells following NFkappaB inhibition.
Main Results:
- TRAIL activates NFkappaB in lymphoid cells with kinetics similar to TNFalpha, independent of FADD, caspases, or apoptosis.
- Inhibition of NFkappaB markedly increased apoptosis sensitivity in susceptible cell lines.
- Antagonizing NFkappaB partially restored apoptosis sensitivity in DIL- and doxorubicin-resistant cell lines and primary leukemia cells.
Conclusions:
- NFkappaB activation plays a survival role against apoptosis induced by DILs and doxorubicin.
- Inhibiting NFkappaB activation can re-sensitize resistant cancer cells to apoptosis.
- Targeting NFkappaB represents a promising strategy to enhance the efficacy of anticancer treatments.