Hepatocyte growth factor promotes cell survival from Fas-mediated cell death in hepatocellular carcinoma cells via Akt activation and Fas-death-inducing signaling complex suppression
Hepatocyte growth factor promotes cell survival from Fas-mediated cell death in hepatocellular carcinoma cells via Akt activation and Fas-death-inducing signaling complex suppression
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DOI：
10.1053/jhep.2000.17738
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发表时间：
2000-10-01
期刊：
影响因子：
13.5
通讯作者：
Shiraki, K
中科院分区：
文献类型：
--
作者：
Suzuki, A;Hayashida, M;Shiraki, K
Akt/PI-3 激酶途径是细胞生存所必需的系统。在当前的研究中，我们发现肝细胞生长因子 (HGF) 激活 Akt/PI-3 激酶通路，抑制人肝细胞癌（HCC；3 系；SK-Hep1、HLE 和 Chang 肝细胞系）、肝母细胞瘤（1 系；HepG2）和胚胎肝细胞（1 系；WRL）中 Fas 介导的细胞死亡。五个测试的细胞系通过 HGF 预处理显示出对 Fas 介导的细胞死亡的抵抗力。这种 HGF 诱导的细胞存活被渥曼青霉素（Akt/PI-3 激酶途径抑制剂）抑制，表明 Akt 参与其中。当用 HGF 预处理细胞时，Fas 介导的细胞死亡被抑制，随后 Ser473 位点的 Akt 磷酸化、Fas 死亡诱导信号复合物 (DISC) 的形成，尤其是 FADD 和 caspase 8 的相互作用，被 HGF 抑制：并且通过 PTEN 的瞬时表达抑制 Akt/PI-3 激酶途径，导致 HGF 处理的细胞中获得 Fas-DISC 形成和 Fas 介导的细胞死亡。我们认为，HGF 通过 Akt 激活导致的 Fas-DISC 抑制，促进肝细胞衍生细胞系（HCC、肝母细胞瘤和胚胎肝细胞）中 Fas 介导的细胞死亡的细胞存活。
The Akt/PI-3 kinase pathway is a system essential for cell survival. In the current study, we showed that hepatocyte growth factor (HGF) activates the Akt/PI-3 kinase pathway to suppress Fas-mediated cell death in human hepatocellular carcinoma (HCC; 3 lines; SK-Hep1, HLE, and Chang Liver cell lines), hepatoblastoma (1 line; HepG2), and embryonic hepatocyte (1 line; WRL). Five tested cell lines showed the resistance to Fas-mediated cell death by the pretreatment of HGF, This HGF-induced cell survival was suppressed by wortmannin (Akt/PI-3 kinase pathway inhibitor), suggesting an involvement of Akt. When cells were pretreated with HGF, Fas-mediated cell death was suppressed, followed by Akt phosphorylation at Ser473, Fas-death-inducing signaling complex (DISC) formation, especially FADD and caspase 8 interaction, was suppressed by HGF: and the suppression of the Akt/PI-3 kinase pathway by transient expression of PTEN, resulting in acquisition of Fas-DISC formation and Fas-mediated cell death in HGF-treated cells. We suggest that HGF promotes cell survival in hepatocyte-derived cell lines (HCC, hepatoblastoma, and embryonic hepatocyte) from Fas-mediated cell death via Fas-DISC suppression as a result of Akt activation.