Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines.
Cancer Res
; 65(12): 5063-9, 2005 Jun 15.
Article
en En
| MEDLINE
| ID: mdl-15958549
ABSTRACT
Vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in tumor-associated microvascular endothelial cells. We have previously reported that up-regulated Bcl-2 expression in microvascular endothelial cells is sufficient to enhance intratumoral angiogenesis and to accelerate tumor growth. We initially attributed these results to Bcl-2-mediated endothelial cell survival. However, in recent experiments, we observed that conditioned medium from Bcl-2-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-2) is sufficient to induce potent neovascularization in the rat corneal assay, whereas conditioned medium from empty vector controls (HDMEC-LXSN) does not induce angiogenesis. These results cannot be attributed to the role of Bcl-2 in cell survival. To understand this unexpected observation, we did gene expression arrays that revealed that the expression of the proangiogenic chemokines interleukin-8 (CXCL8) and growth-related oncogene-alpha (CXCL1) is significantly higher in HDMEC exposed to VEGF and in HDMEC-Bcl-2 than in controls. Inhibition of Bcl-2 expression with small interfering RNA-Bcl-2, or the inhibition of Bcl-2 function with small molecule inhibitor BL-193, down-regulated CXCL8 and CXCL1 expression and caused marked decrease in the angiogenic potential of endothelial cells without affecting cell viability. Nuclear factor-kappaB (NF-kappaB) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-kappaB down-regulated CXCL8 and CXCL1 expression levels. These results reveal a novel function for Bcl-2 as a proangiogenic signaling molecule and suggest a role for this pathway in tumor angiogenesis.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Interleucina-8
/
FN-kappa B
/
Neovascularización Fisiológica
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Proteínas Proto-Oncogénicas c-bcl-2
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Quimiocinas CXC
/
Péptidos y Proteínas de Señalización Intercelular
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos