Rapamycin inhibits proliferation of human neuroblastoma cells without suppression of MycN

Int J Cancer. 2003 Mar 20;104(2):233-7. doi: 10.1002/ijc.10914.


MYCN and insulin-like growth factor (IGF) system are important for the pathogenesis and development of neuroblastoma. We previously reported evidence of a direct linkage between MycN and the IGF system in KP-N-RT human neuroblastoma cells, where IGF-I induced both MycN expression at the RNA level and G1-S cell cycle progression through the IGF-I receptor (IGF-IR)/ MEK/ mitogen-activated protein kinase (MAPK) pathway (A. Misawa et al., Cancer Res, 2000; 60:64-9). Our data also showed the possibility of a potent IGF-IR downstream signal cascade that accelerates progression into the S-phase, other than the MAPK pathway. In this study, we further investigated the role of this alternative pathway in the growth of neuroblastoma cells. A phosphoinositide 3-kinase (PI3K) inhibitor wortmannin blocked IGF-I-mediated induction of MycN. Our data suggest that the inhibition of MycN by wortmannin was transmitted through the MAPK pathway. Progression of the cell cycle from G1 to S phase was inhibited up to 90% by wortmannin or rapamycin, an inhibitor of mTOR, which acts downstream of PI3K. Despite its effects on induction of MycN and on progression through S phase, wortmannin did not block proliferation of neuroblastoma cells. On the other hand, rapamycin inhibited both IGF-I-induced cell cycle progression and cell proliferation in complete medium, although it had no effect on IGF-I-mediated MycN induction. Our study indicates maintenance of cell proliferation requires mTOR function, which is independent of MycN induction in human neuroblastoma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Insulin-Like Growth Factor I / antagonists & inhibitors
  • Insulin-Like Growth Factor I / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sirolimus / pharmacology*
  • Time Factors
  • Tumor Cells, Cultured
  • Wortmannin


  • Androstadienes
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Insulin-Like Growth Factor I
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Sirolimus
  • Wortmannin