Lycopene inhibits angiogenesis both in vitro and in vivo by inhibiting MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways.
METHODS
Limited in vitro data show that lycopene may be anti-angiogenic but with unclear mechanisms. Here, we employed ex vivo and in vivo assays to substantiate the anti-angiogenic action of lycopene and determined its molecular mechanisms in human umbilical vein endothelial cells (HUVECs).


RESULTS
The anti-angiogenic activity of lycopene was confirmed by ex vivo rat aortic ring and in vivo chorioallantoic membrane assays. Furthermore, the in vivo matrigel plug assay in mice demonstrated that lycopene implanted s.c. at the highest dose used (400 μg/plug) completely inhibited the formation of vascular endothelial cells induced by vascular endothelial growth factor (VEGF). As expected, lycopene inhibited tube formation, invasion, and migration in HUVECs, and such actions were accompanied by reduced activities of matrix metalloproteinase-2, urokinase-type plasminogen activator, and protein expression of Rac1, and by enhancing protein expression of tissue inhibitors of metalloproteinase-2 and plasminogen activator inhibitor-1. Moreover, lycopene attenuated VEGF receptor-2 (VEGFR2)-mediated phosphorylation of extracellular signal-regulated kinase (ERK), p38, and Akt as well as protein expression of PI3K.


CONCLUSIONS
Our data demonstrate the anti-angiogenic effect of lycopene both in vitro and in vivo. The anti-angiogenic activity of lycopene may involve inhibition of MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways.
Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan.
Man-Ling
ML
Chen
Yu-Hsiu
YH
Lin
Chih-Min
CM
Yang
Miao-Lin
ML
Hu
D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D002338:Carotenoids / Q000378:metabolism*; D054443:Cell Migration Assays; D002465:Cell Movement; D002478:Cells, Cultured; D002642:Chick Embryo; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D000077276:Lycopene; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D002338:Carotenoids; D058539:Phosphatidylinositol 3-Kinase; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D000077276:Lycopene