Sensitization of neuroblastoma cells for trail-induced apoptosis by nf-Kb inhibition

Abstract

The transcription factor nuclear faetor-kappaB (NF-KB) plays a central role in stress-induced transcriptional activation and has been implicated in chemoresistance of cancers. In the present study, we investigated the role of NF-KB in inducible chemoresistance of neuroblastoma. Doxorubicin, VP 16 and the cytotoxic ligand TRAIL trigger NF-KB activation, whereas cisplatin and taxol have no impact on NF-KB activity, Specific inhibition of NF- KB activation by overexpression of dominant-negative mutant IKBα-super-repressor does not alter cell death upon doxorubicin or VP16 treatment, although it prevents doxorubicin- or YP16-mediated NF-KB activation. By comparison, inhibition of TRAIL- stimulated NF-KB activation by IKBα-superrepressor or the small molecule NF-KB inhibitor BMS-345541 significantly enhances TRAIL-induced apoptosis, pointing to an antiapoptotic function of NF-KB in TRAIL-mediated apoptosis. Analysis of signaling pathways reveals that NF-KB inhibition prevents TRAIL-trig- gered up-reguiaflon of Mcl-l, promoting TRAIL-induced cytochrome c release and activation of caspases. Accordingly, knockdown of Mcl-1 by RNA interference significantly enhances TRAIL-induced apoptosis and also increases sensitivity of neuroblastoma cells to CD95- or chemotherapy-induced apoptosis. In conclusion, NF-KB regulates apoptosis in a stimulus-specific manner in neuroblastoma cells and confers protection against TRAIL-induced apoptosis. By demonstrating that NF-KB inhibition sensitizes neuroblastoma cells for TRAIL-induced apoptosis, our findings have important implications. Thus, NF-KB inhibitors may open new perspectives to potentiate the efficacy of TRAIL- based protocols in the treatment of neuroblastoma. © 2008 Wiley-Liss, Inc.