Artikel
The guanylate binding protein-1 is an endogenous terminator of angiogenesis in inflammaton: perspectives for antiangiogenic tumor therapy
Suche in Medline nach
Autoren
Veröffentlicht: | 7. Oktober 2004 |
---|
Gliederung
Text
Introduction
The inhibition of angiogenesis is a promising approach for the treatment of cancer. Inflammatory cytokines (IC) are potent effectors of endothelial cells (EC) but exert both, pro- and antiangiogenic effects. The goal of this study was, to identify the intracellular mediator of the aniangiogenic effcts of IC in endothelial cells, to be exploited for antiangiogenic therapy.
Materials and methods
Molecular display and convential analysis of gene expression in endothelial cells. Recombinant gene expression technology with amphotropic retroviral vectors. Cell biologic analysis of endothelial cell phenotypes.
Results
We identified the human guanylate binding protein-1 (GBP-1) as the key and specific mediator of the antiangiogenic activity of IC on EC. GBP-1 expression was induced by IC, downregulated by angiogenic growth factors, and inversely related with proliferation both in vitro in microvascular and macrovascular EC and in vivo in vessel endothelial cells of Kaposi's sarcoma [Ref. 1]. Experimental modulation of GBP-1 expression demonstrated that GBP-1 mediates selectively the antiproliferative effect of IC, without affecting endothelial cell adhesiveness for monocytes. GBP-1 antiproliferative activity did not affect ERK-1/2, SAPK/JNK, p38 and NFKB activation, occurred in the absence of apoptosis, was found to be independent of the GTPase activity and isoprenylation of the molecule, but was specifically mediated by the C-terminal helical domain of the protein [Ref. 2]. In addition, GBP-1 inhibited the expression of matrix metalloproteinase-1 (MMP-1) in EC [Ref. 3]. For this effect the GTPase activity of GBP-1 was necessary. A GTPase deficient mutant operated as a transdominant inhibitor (TDI-GBP-1) of wild type GBP-1 and rescued MMP-1 expression in the presence of IC. Expression of TDI-GBP-1 as well as paracrine supplementation of MMP-1 restored the tube forming capability of EC in the presence of the wild type protein.
Conclusion
These findings demonstrate that the helical domain of GBP-1 inhibits EC proliferation and does not affect the capability of EC to form capillaries, whereas the GTPase activity is required for the inhibition of capillary formation but does not affect cell proliferation.These results define GBP-1 as an important terminator of inflammatory angiogenesis that may also be used for antiangiogenic treatment of cancer.