The inhibition of activated hepatic stellate cells proliferation by arctigenin through G0/G1 phase cell cycle arrest: persistent p27(Kip1) induction by interfering with PI3K/Akt/FOXO3a signaling pathway.

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 G0/G1 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 G1 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.

Li A ，Wang J ，Wu M ，Zhang X ，Zhang H ... -  《-》

The PI3K/Akt/FOXO3a/p27Kip1 signaling contributes to anti-inflammatory drug-suppressed proliferation of human osteoblasts.

Akt has been reported to suppress p27(Kip1) promoter activity through Forkhead box O (FOXO) in different kinds of cells. Previous studies indicated that anti-inflammatory drugs up-regulated p27(Kip1), and this effect might play an important role in anti-inflammatory drug-induced cell cycle arrest of human osteoblasts (hOBs). In this study, we hypothesized that these drugs might increase p27(Kip1) expression in hOBs by altering the Akt/FOXO signaling. We tested this hypothesis by examining the influences of three anti-inflammatory drugs on the levels and/or activities of Akt, FOXO and p27(Kip1) as well as the relationship between these factors and proliferation of hOBs. We tested the effects of indomethacin (10(-5) and 10(-4)M), celecoxib (10(-6) and 10(-5)M), and dexamethasone (10(-7) and 10(-6)M) using PI3K inhibitor, LY294002 (10(-5)M) as the basis of comparison. The three drugs suppressed the canonical level of phosphorylated Akt in hOBs. This was accompanied by elevated FOXO3a level and increased promoter activity, mRNA expression and protein level of p27(Kip1). Furthermore, the anti-inflammatory drugs suppressed the EGF-induced increases in proliferation, phosphorylation, and nucleus translocation of Akt. Simultaneously, they suppressed EGF-induced decreases of FOXO3a nucleus accumulation and p27(Kip1) mRNA expression. On the other hand, FOXO silencing significantly attenuated the drug-induced up-regulation of p27(Kip1) and suppression of proliferation in hOBs. To the best of our knowledge, this study represents the first to demonstrate that Akt/FOXO3a/p27(Kip1) pathway contributes to suppression of hOB proliferation by anti-inflammatory drugs. We suggest that anti-inflammatory drugs suppress hOB proliferation, at least partly, through inactivating Akt, activating FOXO3a, and eventually up-regulating p27(Kip1) expression.

Li CJ ，Chang JK ，Chou CH ，Wang GJ ，Ho ML ... -  《-》

Proliferation of murine c-kit(pos) cardiac stem cells stimulated with IGF-1 is associated with Akt-1 mediated phosphorylation and nuclear export of FoxO3a and its effect on downstream cell cycle regulators.

Johnson AM ，Kartha CC 《-》

Co-depletion of cathepsin B and uPAR induces G0/G1 arrest in glioma via FOXO3a mediated p27 upregulation.

Gopinath S ，Malla RR ，Gondi CS ，Alapati K ，Fassett D ，Klopfenstein JD ，Dinh DH ，Gujrati M ，Rao JS ... -  《PLoS One》

PI3K/Akt/FOXO3a pathway contributes to thrombopoietin-induced proliferation of primary megakaryocytes in vitro and in vivo via modulation of p27(Kip1).

Nakao T ，Geddis AE ，Fox NE ，Kaushansky K ... -  《-》