N-Myc overexpression leads to decreased beta1 integrin expression and increased apoptosis in human neuroblastoma cells

Oncogene. 2003 May 1;22(17):2664-73. doi: 10.1038/sj.onc.1206362.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / physiology*
  • Humans
  • In Vitro Techniques
  • Insulin-Like Growth Factor I / metabolism
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism*
  • Mannitol / metabolism
  • Neuroblastoma / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction / physiology*
  • Tumor Cells, Cultured

Substances

  • Integrin beta1
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Mannitol
  • Insulin-Like Growth Factor I