Sensitization of neuroblastoma cells for TRAIL-induced apoptosis by NF-κB inhibition

✍ Scribed by Johannes U. Ammann; Christian Haag; Hubert Kasperczyk; Klaus-Michael Debatin; Simone Fulda

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: French
• Weight: 651 KB
• Volume: 124
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.24068

✦ Synopsis

Abstract

The transcription factor nuclear factor‐kappaB (NF‐κB) 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‐κB in inducible chemoresistance of neuroblastoma. Doxorubicin, VP16 and the cytotoxic ligand TRAIL trigger NF‐κB activation, whereas cisplatin and taxol have no impact on NF‐κB activity. Specific inhibition of NF‐κB activation by overexpression of dominant‐negative mutant IκBα‐super‐repressor does not alter cell death upon doxorubicin or VP16 treatment, although it prevents doxorubicin‐ or VP16‐mediated NF‐κB activation. By comparison, inhibition of TRAIL‐stimulated NF‐κB activation by IκBα‐superrepressor or the small molecule NF‐κB inhibitor BMS‐345541 significantly enhances TRAIL‐induced apoptosis, pointing to an antiapoptotic function of NF‐κB in TRAIL‐mediated apoptosis. Analysis of signaling pathways reveals that NF‐κB inhibition prevents TRAIL‐triggered up‐regulation of Mcl‐1, 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‐κB regulates apoptosis in a stimulus‐specific manner in neuroblastoma cells and confers protection against TRAIL‐induced apoptosis. By demonstrating that NF‐κB inhibition sensitizes neuroblastoma cells for TRAIL‐induced apoptosis, our findings have important implications. Thus, NF‐κB inhibitors may open new perspectives to potentiate the efficacy of TRAIL‐based protocols in the treatment of neuroblastoma. © 2008 Wiley‐Liss, Inc.