title: DNA-damaging drug-induced apoptosis sensitized by N-myc in neuroblastoma cells.
abstract: Neuroblastoma is one of the most common solid tumours in children (8-10% of all malignancies). Over 22% of cases have N-myc amplification associated with aggressively growing neuroblastomas. Oncogene-induced sensitization of cells to apoptosis is an important mechanism for suppression of tumorigenesis. Tumour suppressors often play a critical role in linking oncogenes to apoptotic machinery. For example, activated p53 then targets both intrinsic and extrinsic pathways to promote apoptosis through transcription-dependent and -independent mechanisms. Understanding of the involved mechanisms has important clinical implications. We have employed DNA-damaging drug-induced apoptosis sensitized by oncogene N-myc as a model. DNA damaging drugs trigger high levels of p53, leading to caspase-9 activation in neuroblastoma cells. Inactivation of p53 protects cells from drug-triggered apoptosis sensitized by N-myc. These findings thus define a molecular pathway for mediating DNA-damaging drug-induced apoptosis sensitized by oncogene, and suggest that inactivation of p53 or other components of this apoptotic pathway may confer drug resistance in neuroblastoma cells. The data also suggests that inactivation of apoptotic pathways through co-operating oncogenes may be necessary for the pathogenesis of neuroblastoma with N-myc amplification.
authors.affiliation: State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, Peoples Republic of China.
authors.forename: Tai
authors.initials: T
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Xiao-Xue
authors.initials: XX
authors.lastname: Ke
authors.forename: Xue-Yang
authors.initials: XY
authors.lastname: Gong
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Wan
authors.forename: Xiang-Wei
authors.initials: XW
authors.lastname: Hao
authors.forename: Man
authors.initials: M
authors.lastname: Xu
authors.forename: Zonghuai
authors.initials: Z
authors.lastname: Xiang
authors.forename: Zhao-Bo
authors.initials: ZB
authors.lastname: Cui
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Cui
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005822:Genetic Vectors; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D004317:Doxorubicin; D053453:Caspase 9