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IB Kinase- Regulates Endothelial Cell Motility and Tumor Angiogenesis

Departments of ¹ Cancer Biology, ² Medicine, ³ Radiation Oncology, and ⁴ Cell and Development Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee

Requests for reprints: P. Charles Lin, Vanderbilt University Medical Center, 712 PRB, 2220 Pierce Avenue, Nashville, TN 37232. Phone: 615-936-1749; Fax: 615-936-1872; E-mail: Charles.lin{at}vanderbilt.edu.

Key Words: angiogenesis • endothelial cell • IKK • NF-B • tumor

The transcription factor nuclear factor-B (NF-B) is constitutively activated in many types of cancers and has been implicated in gene expression important for angiogenesis, tumor growth, progression, and metastasis. Here, we show that the NF-B activator, IB kinase- (IKK), but not IKKβ, promotes endothelial cell motility and tumor angiogenesis. IKK is elevated in tumor vasculature compared with normal endothelium. Overexpression of IKK in endothelial cells promoted cell motility and vascular tubule formation in a three-dimensional culture assay, and conversely, knockdown of IKK in endothelial cells inhibited cell motility, compared with controls. Interestingly, blocking NF-B activation totally abolished IKK-induced angiogenic function. Furthermore, using a tumor and endothelial cell cotransplantation model, we show that overexpression of IKK in endothelial cells significantly increased tumor vascular formation compared with controls, which contributed to increased tumor growth and tumor cell proliferation, and decreased tumor cell apoptosis. Collectively, these findings have identified a new function for IKK through the canonical NF-B pathway in tumor angiogenesis. [Cancer Res 2008;68(24):10223–8]

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