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Open Access Highly Accessed Research article

UCN-01 induces S and G2/M cell cycle arrest through the p53/p21waf1 or CHK2/CDC25C pathways and can suppress invasion in human hepatoma cell lines

Guoyi Wu1, Linan Xu2, Nan Lin3* and Bo Liu1*

Author Affiliations

1 Department of General Surgery, the Lingnan Hospital, the Third Affiliated Hospital, Sun Yat-Sen University, GuangZhou, 510630, PR China

2 Department of Gynecology and Obstetrics, the First Affiliated Hospital, Sun Yat-Sen University, GuangZhou, 510089, PR China

3 Department of Hepatobiliary Surgery, the Third Affiliated Hospital, Sun Yat-Sen University, GuangZhou, 510630, PR China

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BMC Cancer 2013, 13:167  doi:10.1186/1471-2407-13-167

Published: 28 March 2013

Abstract

Background

UCN-01 (7-hydroxystaurosporine), a protein kinase inhibitor, has attracted a great deal of attention as a potent antitumour agent. Several clinical trials of UCN-01 alone or in combination with other agents for different tumour types are currently underway, and some of these trials have had positive results. Hepatocellular carcinoma has high incidence rates and is associated with poor prognosis and high mortality rates.

Methods

Three different hepatoma cell lines (Huh7, HepG2, and Hep3B) were treated with different concentrations of UCN-01, and the anti-tumour effects of UCN-01 were evaluated. Following UCN-01 treatment, cell growth was measured using an MTT assay, cell cycle arrest was assayed using flow cytometry, and the mechanisms of cell cycle arrest and invasion inhibition were investigated through western blotting and a Matrigel invasion assay.

Results

After a 72-h UCN-01 treatment, the growth of different hepatoma cell lines was significantly inhibited in a dose-dependent manner, with IC50 values ranging from 69.76 to 222.74 nM. Flow cytometry results suggested that UCN-01 inhibits proliferation in the hepatoma cells by inducing S and G2/M phase arrest, but not G1/S arrest, which differs from previous reports that used other tumour cell lines. Western blot results illustrated that UCN-01 induces a G2/M phase arrest, regardless of the status of the p53/P21waf1 pathway, whereas the CHK2/CDC25C pathway and the p53/p21waf1 pathway were involved in the UCN-01-induced S phase arrest. UCN-01 remarkably inhibited Huh7 cell invasion in a time-dependent manner. Suppression of Huh7 cell invasion may be due to the down-regulation of phosphorylated β-catenin by UCN-01.

Conclusions

These findings suggest that UCN-01 induces hepatoma cell growth inhibition by regulating the p53/p21waf1 and CHK2/CDC25 pathways. Suppression of Huh7 cell invasion by UCN-01 may be due to the down-regulation of phosphorylated β-catenin. These data lend support for further studies on UCN-01 as a promising anti-HCC candidate.

Keywords:
7-hydroxystaurosporine (UCN-01); G2/M arrest; S arrest; Hepatocellular carcinoma; Anti-cancer drug; Beta-catenin; Tumour invasion and migration