The inhibition of activated hepatic stellate cells proliferation by arctigenin through G sub(0)/G sub(1) phase cell cycle arrest: Persistent p27 super(Kip1) induction by interfering with PI3K/Akt/FOXO3a signaling pathway

• Published in: European journal of pharmacology 2015-01, Vol.747, p.71-87
• Main Authors: Li, Ao, Wang, Jun, Wu, Mingjun, Zhang, Xiaoxun, Zhang, Hongzhi
• Format: Article
• Language: English
• ISSN: 0014-2999
• DOI: 10.1016/j.ejphar.2014.11.040

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 sub(0)/G sub(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 sub(1) phase arrest. In the ATG-treated HSCs, the expression level of p27 super(Kip1) and the formation of CDK2-p27 super(Kip1) complex were also increased. p27 super(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 super(Kip1) in activated HSCs. All the above findings suggested that ATG could increase the levels of p27 super(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. Chemical compounds studied in this article * Arctigenin (PubChem CID: 64981) * Dimethyl sulfoxide (PubChem CID: 679) * LY294002 (PubChem CID: 3973) * SB203580 (PubChem CID: 176155) * U0126 (PubChem CID: 3006531) * PHT-427 (PubChem CID: 44240850) * Propidium iodide (PubChem CID: 104981) * 5-Bromo-2-deoxyuridine (PubChem CID: 6035) * Phenylmethanesulfonyl fluoride (PubChem CID: 4784) * Sodium dodecyl sulfate (PubChem CID: 3423265)