Carcinogenesis Advance Access originally published online on August 5, 2004
Carcinogenesis 2004 25(12):2397-2405; doi:10.1093/carcin/bgh250
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Carcinogenesis vol.25 no.12 © Oxford University Press 2004; all rights reserved.
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FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation
Centre for the Study of Liver Disease and 1 Department of Surgery, 2 Department of Anatomy, 3 Department of Pathology and 4 Institute of Molecular Biology, University of Hong Kong, Pokfulam, Hong Kong, China
5 To whom correspondence should be addressed at: Department of Surgery, University of Hong Kong Medical Centre, L9-55, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong. Tel: +852 2819 9646; Fax: +852 2819 9634; Email: kwanman{at}hkucc.hku.hk
Our aim was to study the anticancer effect of the novel immunomodulator FTY720 in vitro and in vivo by investigation of cell cycle entry, cell cycle regulation, cell survival and apoptosis pathways. Three hepatoma cell lines with different p53 statuses (HepG2, Huh-7 and Hep3B) and one non-tumorigenic immortalized liver cell line (MIHA) were used for an in vitro study. The in vivo effects of FTY720 were evaluated in a nude mouse tumor model. Cell cycle distribution and cell cycle regulator proteins p27Kip1 and cyclin D1, together with the PI3-K/Akt pathway, mitogen-activated protein kinases and cleaved caspase-3 and caspase-9, were evaluated. FTY720 selectively induced cell apoptosis in hepatoma cell lines with overexpression of cleaved caspase-3 and caspase-9, but the same phenomena were not found in MIHA cells. FTY720 induced Akt dephosphorylation at Ser473 mediated by phosphoinositide 3-kinase (PI3-K) inhibition. Dephosphorylation led to down-regulation of p42/p44 and dephosphorylation of Forkhead transcription factor and GSK-3ß and, subsequently, up-regulation of p27Kip1 and down-regulation of cyclin D1. In our in vivo model FTY720 induced apoptosis of tumor cells by down-regulation of the Akt pathway. FTY720 suppressed tumor growth without notable side-effects in normal liver. In conclusion, FTY720 is a novel anticancer agent that induces apoptosis of hepatoma cell lines both in vitro and in vivo through PI3-K-mediated Akt dephosphorylation in a p53-independent manner.
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