title: Green tea catechin, epigallocatechin-3-gallate, inhibits vascular endothelial growth factor angiogenic signaling by disrupting the formation of a receptor complex.
abstract: A potential mechanism by which green tea may prevent cancer development is through the inhibition of angiogenesis. We have shown previously that the green tea catechin, epigallocatechin gallate (EGCG), inhibits endothelial cell tube formation through the inhibition of vascular endothelial growth factor (VEGF)-induced Akt activation and vascular endothelial (VE)-cadherin phosphorylation. Furthermore, EGCG can suppress oxidant-induced production of the proangiogenic cytokine interleukin (IL)-8. To further elucidate the antiangiogenic mechanisms of EGCG, we investigated its regulation of other molecular processes in VEGF-induced signaling in human umbilical vein endothelial cells (HUVECs). We show that EGCG at physiological doses (0.5-10 microM) markedly inhibits the formation of a vascular endothelial growth factor receptor 2 complex formed upon the binding of its ligand VEGF. This disruption results in a significant and dose-dependent decrease in PI3-kinase activity. Electrophoretic mobility shift assay revealed that EGCG decreased the PI3 kinase-dependent activation and DNA-binding ability of NF-kappaB, likely acting through decreasing phosphorylation and degradation of IkappaB. VEGF-induced IL-8 production at the mRNA (real time RT-PCR) and protein levels (ELISA) are also suppressed with EGCG. These results suggest a novel mechanism for green tea's anticancer effects where EGCG can abrogate VEGF signaling by interfering with the formation of a receptor complex, resulting in attenuated mitogenic and angiogenic signaling.
authors.affiliation: Vascular Biology Laboratory, JM USDA Human Nutrition Center on Aging at Tufts University, Boston, MA 02111, USA.
authors.forename: Shaun K
authors.initials: SK
authors.lastname: Rodriguez
authors.forename: Weimin
authors.initials: W
authors.lastname: Guo
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Band
authors.forename: Eric K
authors.initials: EK
authors.lastname: Paulson
authors.forename: Mohsen
authors.initials: M
authors.lastname: Meydani
mesh_terms: D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells; D006801:Humans; D009369:Neoplasms / Q000517:prevention & control; D009389:Neovascularization, Pathologic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D013662:Tea / Q000737:chemistry*; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000502:physiology*
chemical_list: D013662:Tea; D042461:Vascular Endothelial Growth Factor A; D002392:Catechin; C045651:epigallocatechin gallate; D019869:Phosphatidylinositol 3-Kinases