Epidemiological data and experimental studies suggest that catechins of black or green tea with potent antioxidant activity have anticancer properties. Catechins can contribute to cancer prevention not only by the reduction of tumor cell growth, migration and invasion, but also by the inhibition of angiogenesis, an obligatory process for tumor growth. However, the exact molecular mechanism by which green tea catechins inhibit angiogenesis is not known. Using our in vitro tube formation assay by the human microvascular endothelial cells (HMVEC), we have tested the inhibitory effect of catechins on vascular endothelial growth factor (VEGF} signaling during angiogenesis. VEGF signaling is a multicomponent complex comprising vascular endothelial (VE)-cadherin/ b-catenin,/VEGF-receptor 2 (Flk-1/KDR)/ phosphatidylinositol 3'(PI3)-kinase. Specifically, we have found that green tea catechins' inhibition of angiogenesis in HMVEC is mediatedl: 1) by disruption of vascular endothelial (VE)-cadherin/b-catenin complex, and inhibition of Akt phosphorylation, a downstream molecular pathway implicated in angiogenesis, and 2) by inhibition of oxidative stress-induced interleukin (IL)-8 production, a potent angiogenic factor. However, the exact molecular target(s) of catechins on the inhibition of angiogenesis is yet to be elucidated. Given our data we propose the following model: Green tea catechins inhibit angiogenesis through disruption of VE-cadherin/b-catenin complex. The loss of complex formation results in inhibition of VEGF signaling and IL-8 gene expression. We propose to examine this model by testing the hypothesis: a) Green tea catechins disrupt VE-cadherin/ VEGF-receptor/ PI3-kinase complex formation. This hypothesis will be tested by co-immunoprecipitation assays and Western blots; b) Green tea catechins inhibit VEGF-induced PI3-kinase activation. This hypothesis will be examined by the PI3-kinase activity assay; c) Green tea catechins inhibit VEGF-induced IL-8 activation, and that this inhibition is mediated through a decrease in the PI3-kinase/Akt pathway leading to decrease of NF-kB activation. This hypothesis will be tested by blocking the PI3-kinase/Akt pathway using wortmanin inhibition and measuring IL-8 production, IL-8 mRNA expression, and NF-kB activation. Validation of this model would help in better understanding the specific molecular targets of tea catechins' induced inhibition of angiogenesis and in developing future studies to develop cost-effective strategies to fight against cancer.
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