afimoxifene and Neuroblastoma

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.

Topics: Apoptosis; Blotting, Western; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase Inhibitors; Caspases; Cell Survival; Culture Media, Serum-Free; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Neuroblastoma; Oxidative Stress; Phenotype; Phosphorylation; Protein Transport; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Retroviridae; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survivin; Tamoxifen; Tumor Cells, Cultured