IkappaB kinase-alpha regulates endothelial cell motility and tumor angiogenesis.
The transcription factor nuclear factor-kappaB (NF-kappaB) 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-kappaB activator, IkappaB kinase-alpha (IKKalpha), but not IKKbeta, promotes endothelial cell motility and tumor angiogenesis. IKKalpha is elevated in tumor vasculature compared with normal endothelium. Overexpression of IKKalpha in endothelial cells promoted cell motility and vascular tubule formation in a three-dimensional culture assay, and conversely, knockdown of IKKalpha in endothelial cells inhibited cell motility, compared with controls. Interestingly, blocking NF-kappaB activation totally abolished IKKalpha-induced angiogenic function. Furthermore, using a tumor and endothelial cell cotransplantation model, we show that overexpression of IKKalpha 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 IKKalpha through the canonical NF-kappaB pathway in tumor angiogenesis.
DeBusk
Laura M
LM
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Massion
Pierre P
PP
Lin
P Charles
PC
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics; D015854:Up-Regulation
D051550:I-kappa B Kinase