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

J. Kang, P. G. Rychahou, T. A. Ishola, J. M. Mourot, B. M. Evers, D. H. Chung

Research output: Contribution to journalArticle

70 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3999-4007
Number of pages9
JournalOncogene
Volume27
Issue number28
DOIs
StatePublished - Jun 26 2008
Externally publishedYes

Keywords

  • Angiogenesis
  • MYCN
  • Neuroblastoma
  • PI3K/Akt
  • VEGF

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Kang, J., Rychahou, P. G., Ishola, T. A., Mourot, J. M., Evers, B. M., & Chung, D. H. (2008). N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma. Oncogene, 27(28), 3999-4007. https://doi.org/10.1038/onc.2008.15