Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 747, Issue -, Pages 71-87Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2014.11.040
Keywords
Hepatic stellate cell; Arctigenin; Forkheacl box O (FOXO); p27(Kip1); Proliferation; Liver fibrosis
Categories
Funding
- National Natural Science Foundation of China [81001675]
- Chongqing Natural Science Foundation [cstc2014jcyjA10030]
- Scientific and Technological Research Program of Chongqing Municipal Education Commission [KJ120820]
- Undergraduate Training Programs for Innovation and Entrepreneurship in Chongqing [201311660024]
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Proliferation of hepatic stellate cells (HSCs) is vital for the development of fibrosis during liver injury. In this study, we describe that arctigenin (ATG), a major bioactive component of Fructus Arctii, exhibited selective cytotoxic activity via inhibiting platelet-derived growth factor-BB (PDGF-BB)-activated HSCs proliferation and arrested cell cycle at G(0)/G(1) phase, which could not be observed in normal human hepatocytes in vitro. The cyclin-dependent kinase (CDK) 4/6 activities could be strongly inhibited by ATG through down-regulation of cyclin D1 and CDK4/6 expression in early G(1) phase arrest. In the ATG-treated HSCs, the expression level of p27(Kip1) and the formation of CDK2-p27(kip1) complex were also increased. p27(Kip1) silencing significantly attenuated the effect of ATG, including cell cycle arrest and suppression of proliferation in activated HSCs. We also found that ATG suppressed PDGF-BB-induced phosphorylation of Akt and its downstream transcription factor Forkhead box O 3a (FOXO3a), decreased ! binding of FOXO3a to 14-3-3 protein, and stimulated nuclear translocation of FOXO3a in activated HSCs. Furthermore, knockdown of FOXO3a expression by FOXO3a siRNA attenuated ATG-induced up-regulation of p27(Kip1) in activated HSCs. All the above findings suggested that ATG could increase the levels of p27(Kip1) protein through inhibition of Akt and improvement of FOXO3a activity, in turn inhibited the CDK2 kinase activity, and eventually caused an overall inhibition of HSCs proliferation. (C) 2014 Elsevier B.V. All rights reserved.
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