Rapamycin inhibits proliferation of human neuroblastoma cells without suppression of MycN

✍ Scribed by Akiko Misawa; Hajime Hosoi; Kunihiko Tsuchiya; Tohru Sugimoto

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: French
• Weight: 214 KB
• Volume: 104
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.10914

✦ Synopsis

Abstract

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. © 2003 Wiley‐Liss, Inc.