p53-mediated delayed NF-κB activity enhances etoposide-induced cell death in medulloblastoma

• Published in: Cell death & disease Vol. 1; no. 5; p. e41
• Main Authors: Meley, D, Spiller, D G, White, M R H, McDowell, H, Pizer, B, Sée, V
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2010; Nature Publishing Group
• Subjects: 631/250/516/1909; 631/378/1689/1690; 631/80/82; 692/699/67/1059/99; Antibodies; Biochemistry; Biomedical and Life Sciences; Caspases - metabolism; Cell Biology; Cell Culture; Cell Death - drug effects; Cell Line, Tumor; Cerebellar Neoplasms - enzymology; Cerebellar Neoplasms - pathology; Drug Screening Assays, Antitumor; Etoposide - pharmacology; Humans; Immunology; Life Sciences; Medulloblastoma - enzymology; Medulloblastoma - pathology; Models, Biological; NF-kappa B - metabolism; Original; original-article; Phosphorylation - drug effects; Receptors, Death Domain - metabolism; Transcription Factor RelA - metabolism; Tumor Suppressor Protein p53 - metabolism; B; glioblastoma; medulloblastoma; NF; CD95/Fas; p53; DNA damaging agents
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2010.16

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 κ B (NF- κ B) 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- κ B are either less sensitive (NF- κ B mutant) or even completely resistant (p53 mutant) to chemotherapeutic intervention. The optimal cell death was only achieved when both p53 and NF- κ B were switched on. Taken together, our results shed light on the mechanism of NF- κ B 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.