1. ¹University Children's Hospital, Ulm, Germany
2. ²Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

Correspondence: Dr C Beltinger, University Children's Hospital, Eythstr. 24, 89075 Ulm, Germany. E-mail: christian.beltinger@uniklinik-ulm.de

³Current address: Department of Physiological Chemistry, University of Ulm, Germany

Received 14 December 2006; Revised 9 October 2007; Accepted 4 December 2007; Published online 14 January 2008.

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.