FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation
FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation
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DOI：
10.1093/carcin/bgh250
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发表时间：
2004-12-01
期刊：
影响因子：
4.7
通讯作者：
Fan, ST
中科院分区：
文献类型：
--
作者：
Lee, TK;Man, K;Fan, ST
我们的目的是研究新型免疫调节剂FTY 720在体外和体内的抗癌作用，通过调查细胞周期进入，细胞周期调节，细胞存活和凋亡途径。三种具有不同p53状态的肝癌细胞系（HepG 2、Huh-7和Hep 3B）和一种非致瘤永生化肝细胞系（MIHA）用于体外研究。在裸鼠肿瘤模型中评价FTY 720的体内作用。细胞周期分布和细胞周期调节蛋白p27（Kip 1）和细胞周期蛋白D1，连同PI 3-K/Akt通路，促分裂原活化蛋白激酶和裂解的caspase-3和caspase-9，进行了评价。FTY 720可选择性诱导caspase-3和caspase-9过表达的肝癌细胞凋亡，而在MIHA细胞中未发现同样的现象。FTY 720通过抑制磷脂酰肌醇3-激酶（PI 3-K）诱导Akt在Ser 473处脱磷酸化。去磷酸化导致p42/p44的下调和Forkhead转录因子和GSK-3 β的去磷酸化，随后上调p27（Kip 1）和下调细胞周期蛋白D1。在我们的体内模型中，FTY 720通过下调Akt通路诱导肿瘤细胞凋亡。FTY 720在正常肝脏中抑制肿瘤生长而无明显副作用。总之，FTY 720是一种新型的抗癌药物，通过PI 3-K介导的Akt去磷酸化以p53非依赖性的方式在体外和体内诱导肝癌细胞系凋亡。
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.