Neuroblastoma is a childhood tumor thought to arise through improper differentiation of neural crest cells. Increased N-Myc expression in neuroblastoma indicates highly malignant disease and poor patient prognosis. N-myc enhances cell growth, insulin-like growth factor type I receptor (IGF-IR) expression, and tumorigenicity in combination with Bcl-2. Despite these effects, N-Myc overexpression in SHEP neuroblastoma cells (SHEP/N-Myc cells) increases serum-withdrawal and mannitol-induced apoptosis. Although we have previously shown a protective effect of IGF-I in SHEP cells, in SHEP/N-Myc cells IGF-I rescue from mannitol-induced apoptosis is prevented. N-Myc overexpression has little effect on IGF-IR signaling pathways, but results in increased Akt phosphorylation when Bcl-2 is coexpressed. A loss of integrin-mediated adhesion promotes apoptosis in many systems. SHEP/N-Myc cells have dramatically less beta1 integrin expression than control cells, consistent with previous reports. beta1 integrin expression is decreased in more tumorigenic neuroblastoma cells lines, including IMR32 and SH-SY5Y cells. Reintroduction of beta1 integrin into the N-Myc-overexpressing cells prevents mannitol-mediated apoptosis. We speculate that N-Myc repression of beta1 integrin expression leads to a less differentiated phenotype, resulting in increased growth and tumorigenesis if properly supported or apoptosis if deprived of growth sustaining molecules.