- 學位論文
Ellagic acid exerts anti-angiogenesis effects by blocking VEGFR-2 signaling pathway in breast cancer
Ellagic acid exerts anti-angiogenesis effects by blocking VEGFR-2 signaling pathway in breast cancer
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並列摘要
Angiogenesis is one of the essential hallmarks of cancer, typically breast cancer. Signaling from VEGFR-2 is necessary for the execution of VEGF-induced proliferation, migration, and tube formation of cultured endothelial cells in vitro and the onset of angiogenesis on tumors in vivo. Ellagic acid is a naturally existing small molecular polyphenol widely found in fruits and vegetables. It was reported that ellagic aicd interfered with some angiogenesis-dependent pathologies. Yet the mechanisms involved were not fully understood. Thus we analyzed its anti-angiogenesis effects and mechanisms on human breast cancer utilizing in vitro and in vivo methodologies. Besides, the in silico analysis was carried out to further analyze the structure-based interaction between ellagic aicd and VEGFR-2. The influences of ellagic aicd on VEGF-induced endothelial cells were studied by proliferation, tube formation and migration in vitro experiments. Kinase activity assay and western blotting were utilized to explore the effects of ellagic aicd on VEGFR-2 induced signaling pathway. Organ-based chick aortic ring model, in vivo Chorioallantoic membrane model and in vivo breast cancer xenografts were built to determine the anti-angiogenesis effects of ellagic aicd. Besides, software LigandFit algorithm in Discovery Studio 2.1 (Accelrys Inc., San Diego, CA) was applied to further understand the structure-based interaction between ellagic aicd and VEGFR-2. We found that ellagic aicd impeded a series of VEGF-induced angiogenesis processes including proliferation, migration and tube formation of endothelial cells. Besides, it directly inhibited VEGFR-2 tyrosine kinase activity and its downstream signaling pathways including MAPK and PI3K/Akt on endothelial cells. Ellagic aicd also obviously inhibited sprouts formation from chicken aorta and neo-vessel formation in chick chorioallantoic membrane. The growth and the P-VEGFR2 expression in breast tumors treated with ellagic aicd were also significantly suppressed. In the molecular docking simulation experiment, the structure-based interaction of VEGFR-2 with ellagic acid was found to be stable conformation by hydrogen bonds within residues Lys866 and Glu883 as well as by π–π interactions within residue Phe1045 at ATP binding pocket of VEGFR-2 catalytic domain. Taken together, ellagic aicd could exert anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer.