PMID- 16618748
OWN - NLM
STAT- MEDLINE
DCOM- 20060607
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 8
DP  - 2006 Apr 15
TI  - Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial 
      growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma 
      cells.
PG  - 4249-55
AB  - The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) 
      expression in neuroblastoma tumors correlates with metastases, N-myc 
      amplification, and poor clinical outcome. Recently, we have shown that 
      insulin-like growth factor-I and serum-derived growth factors stimulate VEGF 
      expression in neuroblastoma cells via induction of hypoxia-inducible 
      factor-1alpha (HIF-1alpha). Because another marker of poor prognosis in 
      neuroblastoma tumors is high expression of brain-derived neurotrophic factor 
      (BDNF) and its tyrosine kinase receptor, TrkB, we sought to evaluate the 
      involvement of BDNF and TrkB in the regulation of VEGF expression. VEGF mRNA 
      levels in neuroblastoma cells cultured in serum-free media increased after 8 to 
      16 hours in BDNF. BDNF induced increases in VEGF and HIF-1alpha protein, whereas 
      HIF-1beta levels were unaffected. BDNF induced a 2- to 4-fold increase in VEGF 
      promoter activity, which could be abrogated if the hypoxia response element in 
      the VEGF promoter was mutated. Transfection of HIF-1alpha small interfering RNA 
      blocked BDNF-stimulated increases in VEGF promoter activity and VEGF protein 
      expression. The BDNF-stimulated increases in HIF-1alpha and VEGF expression 
      required TrkB tyrosine kinase activity and were completely blocked by inhibitors 
      of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) 
      pathways. These data indicate that BDNF plays a role in regulating VEGF levels in 
      neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal 
      transduction pathways, and/or HIF-1alpha have the potential to inhibit VEGF 
      expression and limit neuroblastoma tumor growth.
FAU - Nakamura, Katsuya
AU  - Nakamura K
AD  - Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 
      20892, USA.
FAU - Martin, Kelly C
AU  - Martin KC
FAU - Jackson, Jennifer K
AU  - Jackson JK
FAU - Beppu, Kiichiro
AU  - Beppu K
FAU - Woo, Chan-Wook
AU  - Woo CW
FAU - Thiele, Carol J
AU  - Thiele CJ
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Messenger)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Brain-Derived Neurotrophic Factor/*pharmacology
MH  - Cell Line, Tumor
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/*metabolism
MH  - MAP Kinase Signaling System
MH  - Neuroblastoma/enzymology/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Kinases/metabolism
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Receptor, trkB/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Vascular Endothelial Growth Factor A/*biosynthesis/genetics
EDAT- 2006/04/19 09:00
MHDA- 2006/06/08 09:00
CRDT- 2006/04/19 09:00
PHST- 2006/04/19 09:00 [pubmed]
PHST- 2006/06/08 09:00 [medline]
PHST- 2006/04/19 09:00 [entrez]
AID - 66/8/4249 [pii]
AID - 10.1158/0008-5472.CAN-05-2789 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Apr 15;66(8):4249-55. doi: 10.1158/0008-5472.CAN-05-2789.