Signaling from p53 to NF-kappaB determines the chemotherapy responsiveness of neuroblastoma.

Neuroblastic (N) type neuroblastoma (NB) is the predominant cell type in NB tumors. Previously, we determined that activated nuclear factor κB (NF-κB) is required for doxorubicin and etoposide to kill N-type NB cells. This study was undertaken to determine how NF-κB is activated by these agents. The results show that p53 protein levels increase within 15 to 30 minutes of treatment. This increase occurs before the degradation of inhibitor of NF-κB (I-κB) a and the NF-κB-dependent activation of gene transcription. Moreover, p53 is necessary for NF-κB activation because cells with inactive p53 were resistant to NF-κB-mediated cell death. This pathway was further defined to show that p53 leads to the activation of MAPK/ERK activity kinase (MEK) 1 through a process that depends on protein synthesis and H-Ras. MEK1, in turn, mediates I-κB kinase activation. Together, these results demonstrate for the first time how NF-κB is activated in NB cells in response to conventional drugs. Furthermore, these findings provide an explanation as to why H-Ras expression correlates with a favorable prognosis in NB and identify intermediary signaling molecules that are targets for discovering treatments for NB that is resistant to conventional agents.