Enterostatin inhibition of angiogenesis: possible role of pAMPK and vascular endothelial growth factor A (VEGF-A).

Abstract

INTRODUCTION:

We utilized a genomic analysis of the response of neuronal GT1-7 cells to enterostatin to identify pathways responsive to this peptide. This information, together with reported properties of the enterostatin receptor, suggested that enterostatin may have an effect on angiogenesis.

METHOD:

To investigate this hypothesis, we studied the effect of enterostatin as an antiangiogenic agent in two angiogenic tissue culture model systems.

RESULTS:

Enterostatin induced a 50% or greater inhibition in the angiogenic response of human fat cells and had a U-shaped bimodal dose-response effect in inhibiting angiogenesis in a human placental vein angiogenesis model. To further understand this response, we tested enterostatin's effect in a human hepatoma cell line (HepG2 cells) that was subjected to glucose deprivation, a condition known to induce angiogenesis in other tumor cell lines. Phosphorylated AMP kinase (pAMPK) levels and vascular endothelial growth factor A (VEGF-A) mRNA expression were elevated robustly after incubation of HepG2 cells in the absence of glucose for 4 h, but 15 min incubation with enterostatin dramatically inhibited this pAMPK activation and reduced VEGF-A gene expression after 1 h incubation with enterostatin. The AMPK activator 5-aminoimidazole-4-carboximide ribonucleoside (AICAR) induced VEGF-A expression.

SUMMARY:

These data suggest that enterostatin has an antiangiogenic effect and suggest that it regulates VEGF-A gene expression through inhibition of AMPK activity.

• Authors: M Park, J Lyons 3rd, H Oh, Y Yu, E A Woltering, F Greenway, D A York
• Journal: International journal of obesity (2005) (Int J Obes (Lond)) Vol. 32 Issue 6 Pg. 922-9 (Jun 2008) ISSN: 1476-5497 [Electronic] England
• PMID: 18301390 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Colipases
• Enzyme Precursors
• Hypoglycemic Agents
• RNA, Messenger
• Ribonucleotides
• Vascular Endothelial Growth Factor A
• Aminoimidazole Carboxamide
• procolipase
• Adenylate Kinase
• AICA ribonucleotide

Topics

• Adenylate Kinase (antagonists & inhibitors, metabolism)
• Aminoimidazole Carboxamide (analogs & derivatives, pharmacology)
• Angiogenesis Inhibitors (pharmacology)
• Blotting, Western
• Cell Line
• Colipases (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Precursors (pharmacology)
• Gene Expression (drug effects)
• Humans
• Hypoglycemic Agents (pharmacology)
• In Vitro Techniques
• Neovascularization, Pathologic (pathology, prevention & control)
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger (analysis)
• Ribonucleotides (pharmacology)
• Subcutaneous Fat, Abdominal (blood supply, drug effects)
• Umbilical Veins (blood supply, drug effects)
• Vascular Endothelial Growth Factor A (genetics, metabolism)