title: Marine algal carotenoids inhibit angiogenesis by down-regulating FGF-2-mediated intracellular signals in vascular endothelial cells.
abstract: Discovery of natural compounds as effective angiogenesis inhibitors has become an important approach in the prevention of cancer. We previously demonstrated the anti-angiogenic potential of two marine algal carotenoids, fucoxanthin and siphonaxanthin. In this study, we evaluated the molecular mechanisms of the anti-angiogenic activity of those two carotenoids using human umbilical vein endothelial cells. This study showed that both fucoxanthin and siphonaxanthin suppress the mRNA expression of fibroblast growth factor 2 (FGF-2) and its receptor (FGFR-1) as well as their trans-activation factor, EGR-1. But, the mRNA expression of VEGFR-2 did not show significant effect by those two carotenoids. Further, those two marine algal carotenoids down-regulate the phosphorylation of FGF-2-mediated intracellular signaling proteins such as ERK1/2 and Akt. Inhibition of FGF-2-mediated intracellular signaling proteins by those carotenoids represses the migration of endothelial cells as well as their differentiation into tube-like structures on Matrigel. These results demonstrate for the first time the possible molecular mechanism underlying the anti-angiogenic effects of fucoxanthin and siphonaxanthin and suggest that these effects are due to the down-regulation of signal transduction by FGFR-1. Our findings imply a new insight into the novel bio-functional property of marine algal carotenoids which should improve current anti-angiogenic therapies in the treatment of cancer and other pro-angiogenic diseases.
authors.affiliation: Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Ponesakki
authors.initials: P
authors.lastname: Ganesan
authors.forename: Kiminori
authors.initials: K
authors.lastname: Matsubara
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sugawara
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirata
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D000460:Chlorophyta / Q000737:chemistry; D015536:Down-Regulation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008386:Marine Biology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015394:Molecular Structure; D018919:Neovascularization, Physiologic / Q000187:drug effects; D000459:Phaeophyceae / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D024341:Xanthophylls / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D024341:Xanthophylls; C025164:fucoxanthin; D016222:Fibroblast Growth Factor 2; C003314:siphonaxanthin; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3