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- Title
N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma.
- Authors
Kang, J.; Rychahou, P. G.; Ishola, T. A.; Mourot, J. M.; Evers, B. M.; Chung, D. H.
- Abstract
Angiogenesis in neuroblastoma (NB) correlates with increased expression of vascular endothelial growth factor (VEGF) and a worse clinical outcome. Other cellular markers, such as Akt activation and MYCN amplification, are also associated with poor prognosis in NB; therefore, we sought to determine the role of N-myc in the regulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/VEGF pathway. PI3K inhibition, using small-molecule inhibitors or phosphatase and tensin homolog adenovirus, led to decreased levels of VEGF mRNA and/or protein by reducing phosphorylation of Akt and mammalian target of rapamycin (mTOR), and attenuating hypoxia-inducible factor 1α expression. Moreover, PI3K inhibition decreased levels of N-myc expression in MYCN-amplified cells. To further clarify the importance of N-myc as a target of PI3K in VEGF regulation, we inhibited N-myc expression by siRNA transfection. MYCN siRNA significantly blocked VEGF secretion, irrespective of serum conditions, in MYCN-amplified NB cells; this effect was enhanced when combined with rapamycin, an mTOR inhibitor. Interestingly, in cells with low-N-myc expression, MYCN siRNA reduction of VEGF secretion was only effective with MYCN overexpression or insulin-like growth factor-1 stimulation. Our results show that N-myc plays an important role in the PI3K-mediated VEGF regulation in NB cells. Targeting MYCN, as a novel effector of PI3K-mediated angiogenesis, has significant potential for the treatment of highly vascularized, malignant NB.Oncogene (2008) 27, 3999–4007; doi:10.1038/onc.2008.15; published online 18 February 2008
- Subjects
NEUROBLASTOMA; NERVOUS system tumors; SARCOMA; NEOVASCULARIZATION; CYTOLOGICAL research
- Publication
Oncogene, 2008, Vol 27, Issue 28, p3999
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2008.15