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 p27(Kip1) 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-3beta and, subsequently, up-regulation of p27(Kip1) 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.