N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma
| Autor: | Dai H. Chung, Joshua M. Mourot, Titilope A. Ishola, Junghee Kang, B. M. Evers, Piotr G. Rychahou |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Angiogenesis Biology Article Gene Expression Regulation Enzymologic Adenoviridae Proto-Oncogene Proteins c-myc Neuroblastoma Phosphatidylinositol 3-Kinases chemistry.chemical_compound Tensins Genetics medicine Humans RNA Messenger Insulin-Like Growth Factor I Phosphorylation RNA Small Interfering neoplasms Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Neovascularization Pathologic Microfilament Proteins Transfection medicine.disease Gene Expression Regulation Neoplastic Vascular endothelial growth factor Vascular endothelial growth factor A chemistry Cancer research Proto-Oncogene Proteins c-akt N-Myc |
| Zdroj: | Oncogene. 27:3999-4007 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2008.15 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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