Signaling from p53 to NF-KB Determines the Chemotherapy Responsiveness of Neuroblastoma1

Neuroblastic (N) type neuroblastoma (NB) is the predominant cell type in NB tumors. Previously, we determined that activated nuclear factor KB (NF-KB) is required for doxorubicin and etoposide to kill N-typeNB cells. This study was undertaken to determine how NF-KB 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-KB (I-KB)A and theNF-KB–dependent activation of gene transcription. Moreover, p53 is nec-essary for NF-KB activation because cells with inactive p53 were resistant to NF-KB–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-KB kinase ac-tivation. Together, these results demonstrate for the first time howNF-KB 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