PMID- 18278068
OWN - NLM
STAT- MEDLINE
DCOM- 20080723
LR  - 20211020
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 27
IP  - 28
DP  - 2008 Jun 26
TI  - N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma.
PG  - 3999-4007
LID - 10.1038/onc.2008.15 [doi]
AB  - 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.
FAU - Kang, J
AU  - Kang J
AD  - Department of Surgery, The University of Texas Medical Branch, Galveston, TX 
      77555-0353, USA.
FAU - Rychahou, P G
AU  - Rychahou PG
FAU - Ishola, T A
AU  - Ishola TA
FAU - Mourot, J M
AU  - Mourot JM
FAU - Evers, B M
AU  - Evers BM
FAU - Chung, D H
AU  - Chung DH
LA  - eng
GR  - R01 DK048498-12/DK/NIDDK NIH HHS/United States
GR  - F31 DK079422/DK/NIDDK NIH HHS/United States
GR  - P01 DK35608/DK/NIDDK NIH HHS/United States
GR  - R01 DK61470/DK/NIDDK NIH HHS/United States
GR  - P01 DK035608-210001/DK/NIDDK NIH HHS/United States
GR  - R01 DK061470/DK/NIDDK NIH HHS/United States
GR  - R01 CA104748-04/CA/NCI NIH HHS/United States
GR  - R01 CA104748/CA/NCI NIH HHS/United States
GR  - R01 DK048498/DK/NIDDK NIH HHS/United States
GR  - P01 DK035608/DK/NIDDK NIH HHS/United States
GR  - R01 DK48498/DK/NIDDK NIH HHS/United States
GR  - R01 DK061470-05/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080218
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Microfilament Proteins)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tensins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Adenoviridae/genetics
MH  - *Gene Expression Regulation, Enzymologic
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Insulin-Like Growth Factor I/metabolism
MH  - Microfilament Proteins/chemistry
MH  - Neovascularization, Pathologic
MH  - Neuroblastoma/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins c-myc/*metabolism
MH  - RNA, Messenger/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Tensins
MH  - Vascular Endothelial Growth Factor A/*metabolism
PMC - PMC2614290
MID - NIHMS53637
EDAT- 2008/02/19 09:00
MHDA- 2008/07/24 09:00
PMCR- 2009/06/26
CRDT- 2008/02/19 09:00
PHST- 2008/02/19 09:00 [pubmed]
PHST- 2008/07/24 09:00 [medline]
PHST- 2008/02/19 09:00 [entrez]
PHST- 2009/06/26 00:00 [pmc-release]
AID - onc200815 [pii]
AID - 10.1038/onc.2008.15 [doi]
PST - ppublish
SO  - Oncogene. 2008 Jun 26;27(28):3999-4007. doi: 10.1038/onc.2008.15. Epub 2008 Feb 
      18.