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Copper chelator ATN-224 inhibits endothelial function by multiple mechanisms
Sarah A Lowndes1, Helen V Sheldon, Shijie Cai
1Cancer Research UK Department of Medical Oncology, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, UK.
Microvascular Research
|March 28, 2009
Summary
Copper chelation therapy using ATN-224 impacts endothelial cell function by altering gene expression and protein activity. This copper-lowering approach may target angiogenesis through regulating aquaporin-1 (AQP1).
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Copper is essential for endothelial cell proliferation and tumor growth.
- Copper-lowering therapy shows promise in reducing tumor growth.
- ATN-224 is a novel copper chelator inhibiting copper-dependent superoxide dismutase 1 (SOD1) in endothelial cells.
Purpose of the Study:
- To investigate the effects of ATN-224 on gene expression in endothelial cells.
- To elucidate the mechanisms by which ATN-224 affects endothelial cell function and angiogenesis.
- To explore the role of aquaporin-1 (AQP1) in copper chelation therapy.
Main Methods:
- Microarray analysis of gene expression in endothelial cells treated with ATN-224.
- Quantitative PCR (qPCR) to confirm gene expression changes.
- RNA interference (siRNA) targeting SOD1 and AQP1.
- Assessment of cellular responses including superoxide levels, signaling pathways, and protein expression.
Main Results:
- ATN-224 upregulated stress response genes (e.g., heme-oxygenase 1) and differentially regulated angiogenesis-implicated genes (e.g., CXCR4, AQP1).
- ATN-224 treatment increased superoxide levels, activated ERK signaling, induced anti-apoptotic proteins, and caused nuclear translocation of SOD1.
- SOD1 RNA interference mimicked some ATN-224 effects but not HO-1 or PGES2 upregulation, suggesting additional mechanisms.
- Downregulation of AQP1 by ATN-224 and SOD1 siRNA was observed; AQP1 knockdown inhibited endothelial proliferation and migration, confirming its role in angiogenesis.
- AQP1 expression could be restored by adding copper, and its downregulation by ATN-224 may be a key action of copper chelation therapy.
Conclusions:
- ATN-224 significantly alters endothelial cell gene expression and function, impacting stress responses and angiogenesis.
- While SOD1 inhibition contributes to ATN-224's effects, other mechanisms are involved.
- Regulation of aquaporin-1 (AQP1) appears to be a critical mechanism through which copper chelation therapy exerts its anti-angiogenic effects.
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