Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-κB and CXC chemokines

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-06, Vol.65 (12), p.5063-5069
• Main Authors: KARL, Elisabeta, WARNER, Kristy, NUNEZ, Gabriel, POLVERINI, Peter J, NÖR, Jacques E, ZEITLIN, Benjamin, KANEKO, Tomoatsu, WURTZEL, Lindsey, TAOCONG JIN, JIA CHANG, SHAOMENG WANG, WANG, Cun-Yu, STRIETER, Robert M
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Medical sciences; Pharmacology. Drug treatments; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-0140

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-α (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-κB (NF-κB) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-κB 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.