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.