NF-κB activation in endothelial cells is critical for the activity of angiostatic agents

SP Tabruyn, S Mémet, P Avé, C Verhaeghe… - Molecular cancer …, 2009 - AACR
SP Tabruyn, S Mémet, P Avé, C Verhaeghe, KH Mayo, I Struman, JA Martial, AW Griffioen
Molecular cancer therapeutics, 2009AACR
In tumor cells, the transcription factor NF-κB has been described to be antiapoptotic and
proproliferative and involved in the production of angiogenic factors such as vascular
endothelial growth factor. From these data, a protumorigenic role of NF-κB has emerged.
Here, we examined in endothelial cells whether NF-κB signaling pathway is involved in
mediating the angiostatic properties of angiogenesis inhibitors. The current report describes
that biochemically unrelated agents with direct angiostatic effect induced NF-κB activation in …
Abstract
In tumor cells, the transcription factor NF-κB has been described to be antiapoptotic and proproliferative and involved in the production of angiogenic factors such as vascular endothelial growth factor. From these data, a protumorigenic role of NF-κB has emerged. Here, we examined in endothelial cells whether NF-κB signaling pathway is involved in mediating the angiostatic properties of angiogenesis inhibitors. The current report describes that biochemically unrelated agents with direct angiostatic effect induced NF-κB activation in endothelial cells. Our data showed that endostatin, anginex, angiostatin, and the 16-kDa N-terminal fragment of human prolactin induced NF-κB activation in endothelial cells in both cultured human endothelial cells and in vivo in a mouse tumor model. It was also found that NF-κB activity was required for the angiostatic activity, because inhibition of NF-κB in endothelial cells impaired the ability of angiostatic agents to block sprouting of endothelial cells and to overcome endothelial cell anergy. Therefore, activation of NF-κB in endothelial cells can result in an unexpected antitumor outcome. Based on these data, the current approach of systemic treatment with NF-κB inhibitors may therefore be revisited because NF-κB activation specifically targeted to endothelial cells might represent an efficient strategy for the treatment of cancer. [Mol Cancer Ther 2009;8(9):2645–54]
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