Ligularia fischeri inhibits endothelial cell proliferation, invasion and tube formation through the inactivation of mitogenic signaling pathways and regulation of vascular endothelial cadherin distribution and matrix metalloproteinase expression

Abstract

Abstract. Ligularia fischeri (LF) has been used as an edible herb and traditional medicine for the treatment of inflammatory and infectious diseases. In the present study, we report the effects and molecular mechanism of the ethanolic extract of LF on cell proliferation, invasion and tube formation in human umbilical vein endothelial cells (HUVECs). LF-mediated inhibition of cell proliferation was accompanied by reduced expression of cell cycle-related proteins such as cyclin-dependent kinases (Cdks) and cyclins, leading to pRb hypophosphorylation and G 1 phase cell cycle arrest. We also show that LF treatment inhibited cell invasion and tube formation in HUVECs. These anti-angiogenic activities of LF were associated with the inactivation of mitogenic signaling pathways, induction of vascular endothelial (VE)-cadherin distribution at cell-cell contacts and inhibition of matrix metalloproteinase (MMP) expression. Collectively, our findings demonstrate the pharmacological functions and molecular mechanisms of LF in regulating endothelial cell fates, and support further development as a potential therapeutic agent for the treatment and prevention of angiogenesis-related disorders including cancer. IntroductionAngiogenesis, the formation of new blood vessels from pre-existing neighboring vessels, is essential for pathological conditions including cancer, ocular disorders, arthritis and obesity as well as physiological processes such as wound-healing, menstruation and ovulation (1,2). The process of angiogenesis includes endothelial cell proliferation, migration, adhesion, invasion, tube formation and recruitment of pericytes, and is tightly regulated by the complex interplay of angiogenic and anti-angiogenic factors within tissue microenvironment (3-5). Matrix metalloproteinases (MMPs) play important roles in tissue remodeling by degrading extracellular matrix (ECM) components and cell surface molecules, leading to angiogenic responses associated with cancer growth and progression (6-8). MMP-mediated cleavage of vascular endothelial (VE)-cadherin in cell surfaces may promote vascular permeability, proliferation, invasion and capillary-like structure formation by dissociating cadherin-catenin complex and disrupting cell-cell adhesion (9-14). The activities of these MMPs are regulated by endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs) (15). In addition to MMP-inhibitory activity, many investigations demonstrate that TIMPs regulate cell fates such as proliferation, migration, apoptosis and differentiation through MMP-independent mechanism (16)(17)(18)(19)(20)(21)

Antihyperglycemic and Antilipidemic Effects of the Ethanol Extract Mixture of Ligularia fischeri and Momordica charantia in Type II Diabetes‐Mimicking Mice

“…As a nonmedicinal alternative, MCE has been found to be a good functional food for diabetes intervention [ 14 ], but its potential as a remedy for diabetes has not been fully determined . The leaves of L. fischeri are another edible herb distributed throughout Eastern Asia including Korea, China, and Japan and are used as a traditional medicine for the treatment of inflammatory and infectious diseases, as well as obesity [ 26 , 27 ]. Here, we demonstrated the antidiabetic potential of LFE based on its ability to decrease blood glucose, TG, T-Chol, and NEFA levels in STZ/ATH mice ( Table 6 ).…”

Trigonostemon reidioides modulates endothelial cell proliferation, migration and tube formation via downregulation of the Akt signaling pathway

“…The PI3K/Akt signaling pathway serves pivotal roles in the growth, migration and formation of blood vessels in endothelial cells ( 11 , 12 ). Our group has previously reported that the ethanolic extracts of Ligularia fischeri and Broussonetia kazinoki inhibited the proliferation, invasion and tube formation of endothelial cells by inactivation of the mitogen- and VEGF-A-stimulated signaling pathways, including the PI3K/Akt signaling pathway ( 37 , 38 ). To the best of our knowledge, the present study demonstrated for the first time that ETR inhibited mitogen-induced endothelial cell proliferation, adhesion, migration, invasion and tube formation.…”

5-Caffeoylquinic acid inhibits invasion of non-small cell lung cancer cells through the inactivation of p70S6K and Akt activity: Involvement of p53 in differential regulation of signaling pathways

“…(Compositae) has been used as a traditional medicine for the treatment of rheumatoid arthritis, scarlet fever and jaundice in eastern Asia including Korea, China and Japan. Previous investigations demonstrate that L. fischeri extract and its bioactive components such as caffeic acid and chlorogenic acid isomers possess anti-oxidant, anti-inflammatory, anti-angiogenic and anticancer properties (9)(10)(11). Chlorogenic acid isomers including 5-caffeoylquinic acid (5-CQA), which have been identified in a variety of plants including green coffee beans, walnut (Juglans regia L.) leaves, yerba-mate (Ilex paraguariensis) extract, Petasites japonicus extract and Marrubium vulgare extract as well as L. fischeri extract, have been known to exert a variety of biological functions such as anti-oxidant, anti-microbial, anti-diabetic, anti-inflammatory and anticancer activities (12)(13)(14)(15)(16)(17)(18)(19).…”