Tumor-biological significance of Myc-relarted gene products in neuroblastoma cells

点击翻译按钮获取中文摘要

Insulin-like growth factor I (IGF-I) stimulates proliferation, survival and differentiation in many cell types, including the pediatric neuroblastomas. The effect is mediated via the type I IGF-I receptor (IGF-IR), which is essential for growth in these cells. Several lines of evidence indicated that IGF-IR function may be particular important in the pathogenesis of the neuroblastoma. Amplification of the N-myc oncogene or overexpression of N-Myc oncoprotein have been reported to be associated with resistance to therapy and poor prognosis of neuroblastomas. It was therefore of interest to analyze whether IGF-I signaling regulated expression on N-myc in KP-N-RT human neuroblastoma cells as an experimental model that has amplified N-myc. We found that IGF-I induces N-myc mRNA and protein in the KP-N-RT with the maximum of 4 and 6 times more than the basal level at 2 and 3 hrs after the stimulation, respectively. These effects of IGF-I were blocked by a neutralizing antibody against IGF-IR (α-IR3). Exogenous IGF-I induced phosphorylation of extracellular signal-regulated kinases p42/44 (Erk1 and Erk2), with a maximal level 30 min after the stimulation. The MEK1 inhibitor PD98059 reduced IGF-I-mediated p42/44 tyrosine phosphorylation, and produced a parallel reduction of IFG-I-stimulated N-Myc induction. Furthermore, both α-IR3 and PD98059 inhibited G1-S cell cycle progression stimulated by IGF-I. Our results demonstrate that IGF-I induces N-Myc in the KP-N-RT neuroblastoma cell line at the RNA level and establishes a clear correlation between N-Myc induction and activation of p42/44 MAPK signaling.