title: N-myc augments death and attenuates protective effects of Bcl-2 in trophically stressed neuroblastoma cells.
abstract: N-myc has proapoptotic functions, yet it acts as an oncogene in neuroblastoma. Thus, antiapoptotic mechanisms have to be operative in neuroblastoma cells that antagonize the proapoptotic effects of N-myc. We conditionally activated N-myc in SH-EP neuroblastoma cells subjected to the trophic stress of serum or nutrient deprivation while changing the expression of Bcl-2, survivin and FLIP(L), antiapoptotic molecules often overexpressed in poor prognosis neuroblastomas. Bcl-2 protected SH-EP cells from death during nutritional deprivation by activating energetically advantageous oxidative phosphorylation. N-myc overrode the metabolic protection provided by Bcl-2-induced oxidative phosphorylation by reestablishing the glycolytic phenotype and attenuated the antiapoptotic effect of Bcl-2 during metabolic stress. Survivin partially antagonized the growth suppressive function of N-myc in SH-EP neuroblastoma cells during serum deprivation whereas FLIP(L) did not. These findings advance our understanding of the functions of N-myc in neuroblastoma cells.
authors.affiliation: University Children's Hospital, Ulm, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ushmorov
authors.forename: M D
authors.initials: MD
authors.lastname: Hogarty
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Knauss
authors.forename: K M
authors.initials: KM
authors.lastname: Debatin
authors.forename: C
authors.initials: C
authors.lastname: Beltinger
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D010766:Phosphorylation; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; D016895:Culture Media, Serum-Free; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D000077022:Survivin; D013629:Tamoxifen; C016601:afimoxifene; D020169:Caspases