title: Signaling from p53 to NF-kappaB determines the chemotherapy responsiveness of neuroblastoma.
abstract: Neuroblastic (N) type neuroblastoma (NB) is the predominant cell type in NB tumors. Previously, we determined that activated nuclear factor kappaB (NF-kappaB) is required for doxorubicin and etoposide to kill N-type NB cells. This study was undertaken to determine how NF-kappaB 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-kappaB (I-kappaB) alpha and the NF-kappaB-dependent activation of gene transcription. Moreover, p53 is necessary for NF-kappaB activation because cells with inactive p53 were resistant to NF-kappaB-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-kappaB kinase activation. Together, these results demonstrate for the first time how NF-kappaB 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.
authors.affiliation: Department of Pediatrics, University of Michigan Medical School and the University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109-0983, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Armstrong
authors.forename: Xin
authors.initials: X
authors.lastname: Bian
authors.forename: Yihong
authors.initials: Y
authors.lastname: Liu
authors.forename: Chitra
authors.initials: C
authors.lastname: Subramanian
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Ratanaproeksa
authors.forename: Feng
authors.initials: F
authors.lastname: Shao
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yu
authors.forename: Roland P S
authors.initials: RP
authors.lastname: Kwok
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Opipari
authors.forename: Valerie P
authors.initials: VP
authors.lastname: Castle
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism*; D011379:Prognosis; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048369:MAP Kinase Kinase 1