4662

In the classical pathway of Nuclear Factor-kappa B (NF-κB) activation, NF-κB subunits are sequestered in the cytoplasm by the Inhibitor of Kappa B (IKB) and released to the nucleus when IKB is phosphorylated by the Inhibitor of Kappa B kinase (IKK) complex. The IKK complex consists of the regulatory IKKγ subunit, along with a dimer of IKKα subunits, IKKβ subunits, or both an IKKα and IKKβ subunit. In this study, our lab showed that IKKα specific induction of NF-κB translocation to the nucleus promoted a pro-angiogenic phenotype in endothelial cells (ECs) in vitro and in vivo through the classical NF-κB signaling pathway. IKKα expression, but not IKKβ expression, increased cell motility and tube formation in endothelial cells (ECs). This pro-angiogenic phenotype could be blocked with the co-expression of IKB, demonstrating that IKKα induction of NF-κB translocation was through the classical pathway. We also found that IKKα activation had a pro-angiogenic effect in vivo. We subcutaneously injected Rag-1 mice with matrigel containing Lewis Lung Carcinoma (LLC) cells alone or LLC cells mixed with either IKKα-expressing or GFP-expressing ECs. Tumor size was measured daily, and tissue was harvested for analysis. We found that LLC cells mixed with IKKα-expressing ECs formed palpable tumors earlier than control tumors and tumors containing IKKα-expressing ECs initially grew much larger than controls. The vascular density was significantly higher, and there were fewer hypoxic regions in tumors containing IKKα-expressing ECs than in control tumors. Tumor cell growth was significantly higher and apoptosis was significantly lower in these tumors compared to control tumors. The data demonstrates that IKKα activation in ECs plays an important role in tumor angiogenesis. IKKα-expressing ECs induced a pro-angiogenic phenotype in ECs in vitro and increased the levels of tumor angiogenesis as demonstrated by an increase vascular density in tumor tissue. The increase in tumor angiogenesis promoted cell growth and lowered the levels of apoptosis in tumor tissue. Thus the expression and activation of IKKα provide potential new targets for anti-angiogenic cancer therapies.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]