Document Detail

p53-mediated delayed NF-κB activity enhances etoposide-induced cell death in medulloblastoma.
MedLine Citation:
PMID:  21364648     Owner:  NLM     Status:  MEDLINE    
Medulloblastoma (MB) is an embryonic brain tumour that arises in the cerebellum. Using several MB cell lines, we have demonstrated that the chemotherapeutic drug etoposide induces a p53- and caspase-dependent cell death. We have observed an additional caspase-independent cell death mechanism involving delayed nuclear factor κB (NF-κB) activity. The delayed induction was controlled by a p53-dependent transcription step and the production of death receptors (especially CD95/Fas). We further demonstrated that in both MB and glioblastoma (GM) cell lines, in which the p53 pathway was not functional, no p65 activation could be detected upon etoposide treatment. MB cell lines that have mutations in p53 or NF-κB are either less sensitive (NF-κB mutant) or even completely resistant (p53 mutant) to chemotherapeutic intervention. The optimal cell death was only achieved when both p53 and NF-κB were switched on. Taken together, our results shed light on the mechanism of NF-κB activation by etoposide in brain tumours and show that the genetic background of MB and GM cells determines their sensitivity to chemotherapy and has to be taken into account for efficient therapeutic intervention.
D Meley; D G Spiller; M R H White; H McDowell; B Pizer; V Sée
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-13
Journal Detail:
Title:  Cell death & disease     Volume:  1     ISSN:  2041-4889     ISO Abbreviation:  Cell Death Dis     Publication Date:  2010  
Date Detail:
Created Date:  2011-03-02     Completed Date:  2011-09-15     Revised Date:  2014-10-14    
Medline Journal Info:
Nlm Unique ID:  101524092     Medline TA:  Cell Death Dis     Country:  England    
Other Details:
Languages:  eng     Pagination:  e41     Citation Subset:  IM    
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MeSH Terms
Caspases / metabolism
Cell Death / drug effects
Cell Line, Tumor
Cerebellar Neoplasms / enzymology,  pathology*
Drug Screening Assays, Antitumor
Etoposide / pharmacology*
Medulloblastoma / enzymology,  pathology*
Models, Biological
NF-kappa B / metabolism*
Phosphorylation / drug effects
Receptors, Death Domain / metabolism
Transcription Factor RelA / metabolism
Tumor Suppressor Protein p53 / metabolism*
Grant Support
BB/F005938/1//Biotechnology and Biological Sciences Research Council; BBC5204711//Biotechnology and Biological Sciences Research Council
Reg. No./Substance:
0/NF-kappa B; 0/Receptors, Death Domain; 0/Transcription Factor RelA; 0/Tumor Suppressor Protein p53; 6PLQ3CP4P3/Etoposide; EC 3.4.22.-/Caspases

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