Abstract |
Hypoxia is a general characteristic of most solid malignancies and intimately related to neoplastic diseases and cancer progression. Homeostatic response to hypoxia is primarily mediated by hypoxia inducible factor (HIF)-1α that elicits transcriptional activity through recruitment of the CREB binding protein (CBP)/p300 coactivator. Targeted blockade of HIF-1α binding to CBP/p300 would thus constitute a novel approach for cancer treatment by suppressing tumor angiogenesis and metastasis. Here, we identified inhibitors against the interaction between HIF-1α and p300 by a fluorescence polarization-based assay employing a fluorescently-labeled peptide containing the C-terminal activation domain of HIF-1α. Two small molecule inhibitors, menadione (MD) and ethacrynic acid (EA), were found to decrease expression of luciferase under the control of hypoxia-responsive elements in hypoxic cells as well as to efficiently block the interaction between the full-length HIF-1α and p300. While these compounds did not alter the expression level of HIF-1α, they down-regulated expression of a HIF-1α target vascular endothelial growth factor ( VEGF) gene. Considering hypoxia-induced VEGF expression leading to highly aggressive tumor growth, MD and EA may provide new scaffolds for development of tumor therapeutic reagents as well as tools for a better understanding of HIF-1α-mediated hypoxic regulation.
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Authors | Yu-Ran Na, Ki-Cheol Han, Hyunsung Park, Eun Gyeong Yang |
Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 434
Issue 4
Pg. 879-84
(May 17 2013)
ISSN: 1090-2104 [Electronic] United States |
PMID | 23618863
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Elsevier Inc. All rights reserved. |
Chemical References |
- Hypoxia-Inducible Factor 1, alpha Subunit
- Vascular Endothelial Growth Factor A
- Vitamin K 3
- Luciferases
- E1A-Associated p300 Protein
- EP300 protein, human
- Ethacrynic Acid
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Topics |
- Binding Sites
(genetics)
- Cell Hypoxia
- Cell Survival
(drug effects)
- Dose-Response Relationship, Drug
- E1A-Associated p300 Protein
(genetics, metabolism)
- Ethacrynic Acid
(chemistry, pharmacology)
- Gene Expression
(drug effects)
- HeLa Cells
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(genetics, metabolism)
- Immunoblotting
- Luciferases
(genetics, metabolism)
- Molecular Structure
- Protein Binding
(drug effects)
- Protein Interaction Mapping
(methods)
- Response Elements
(genetics)
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
(drug effects)
- Vascular Endothelial Growth Factor A
(genetics)
- Vitamin K 3
(chemistry, pharmacology)
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