N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma

Oncogene. 2008 Jun 26;27(28):3999-4007. doi: 10.1038/onc.2008.15. Epub 2008 Feb 18.


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 1alpha 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoviridae / genetics
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Microfilament Proteins / chemistry
  • Neovascularization, Pathologic
  • Neuroblastoma / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Tensins
  • Vascular Endothelial Growth Factor A / metabolism*


  • Microfilament Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • RNA, Small Interfering
  • Tensins
  • Vascular Endothelial Growth Factor A
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt