Regulation of Tie2 During VEGI-Mediated Inhibition of Angiogenesis

摘要

The endothelial receptor tyrosine kinase Tie2 is highly overexpressed in breast cancer and its overexpression is significantly correlated with metastasis and poor outcome. Vascular endothelial growth inhibitor (VEGI), a novel antiangiogenic agent that inhibits breast cancer growth and angiogenesis, can maintain G0/G1 arrest of synchronized endothelial cells (EC) and induce apoptosis in proliferating EC. We have observed that VEGI can regulate expression of Tie2, reducing protein level about 50% during growth arrest, but rapidly eliminating its expression in proliferating cells induced by VEGI to undergo apoptosis. This proposal examines the hypothesis that VEGI inhibits angiogenesis by inhibition of Tie2 signaling. We have shown that VEGI signaling is dominant to AKT signaling, as VEGI can attenuate Angiopoietin-1 (Ang1)- mediated activation of Akt in apoptotic cells, and that prior stimulation of Tie2 by Ang1 cannot prevent VEGI-mediated downregulation of Tie2 or prevent apoptosis. Further, overexpression of Tie2 only slightly attenuates VEGI- mediated apoptosis, while overexpression of myr-AKT does confer some protection. Mechanistically, we have determined that the downregulation of Tie2 is controlled by both decreased RNA expression as well as group I caspase-mediated cleavage of existing Tie2 protein during apoptosis. These data suggest that VEGI may be an effective agent against Tie2 overexpressing tumor vasculature.