Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo
- 19 November 2007
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 27 (20), 2910-2922
- https://doi.org/10.1038/sj.onc.1210938
Abstract
Mammalian target of rapamycin (mTOR) has been shown to play an important function in cell proliferation, metabolism and tumorigenesis, and proteins that regulate signaling through mTOR are frequently altered in human cancers. In this study we investigated the phosphorylation status of key proteins in the PI3K/AKT/mTOR pathway and the effects of the mTOR inhibitors rapamycin and CCI-779 on neuroblastoma tumorigenesis. Significant expression of activated AKT and mTOR were detected in all primary neuroblastoma tissue samples investigated, but not in non-malignant adrenal medullas. mTOR inhibitors showed antiproliferative effects on neuroblastoma cells in vitro. Neuroblastoma cell lines expressing high levels of MYCN were significantly more sensitive to mTOR inhibitors compared to cell lines expressing low MYCN levels. Established neuroblastoma tumors treated with mTOR inhibitors in vivo showed increased apoptosis, decreased proliferation and inhibition of angiogenesis. Importantly, mTOR inhibitors induced downregulation of vascular endothelial growth factor A (VEGF-A) secretion, cyclin D1 and MYCN protein expression in vitro and in vivo. Our data suggest that mTOR inhibitors have therapeutic efficacy on aggressive MYCN amplified neuroblastomas.Keywords
This publication has 36 references indexed in Scilit:
- Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivoClinical Cancer Research, 2007
- Inhibition of Phosphatidylinositol 3-Kinase Destabilizes Mycn Protein and Blocks Malignant Progression in NeuroblastomaCancer Research, 2006
- Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesisNature Reviews Cancer, 2006
- Exploiting the PI3K/AKT Pathway for Cancer Drug DiscoveryNature Reviews Drug Discovery, 2005
- Proliferation of Human Neuroblastomas Mediated by the Epidermal Growth Factor ReceptorCancer Research, 2005
- Ras and Myc can drive oncogenic cell proliferation through individual D-cyclinsOncogene, 2005
- Pterin-Dependent Tyrosine Hydroxylase mRNA is not Expressed in Human Melanocytes or Melanoma CellsPigment Cell Research, 2004
- Insulin-like growth factor-I signaling in human neuroblastoma cellsOncogene, 2004
- Evidence That Cyclin D1 Mediates Both Growth and Proliferation Downstream of TOR in HepatocytesPublished by Elsevier BV ,2003
- Regulation of cell size in growth, development and human disease: PI3K, PKB and S6KBioEssays, 2002