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

Authors

  • Atsushi Suzuki,

    1. Project for the Cell Death Research, Basic Technology Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center, Tokyo, Japan
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  • Midori Hayashida,

    1. Project for the Cell Death Research, Basic Technology Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center, Tokyo, Japan
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  • Hirokazu Kawano,

    1. Project for the Cell Death Research, Basic Technology Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center, Tokyo, Japan
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  • Kazushi Sugimoto,

    1. The First Department of Internal Medicine, Mie University School of Medicine, Mie, Japan
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  • Takeshi Nakano,

    1. The First Department of Internal Medicine, Mie University School of Medicine, Mie, Japan
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  • Katsuya Shiraki

    Corresponding author
    1. The First Department of Internal Medicine, Mie University School of Medicine, Mie, Japan
    • Project for the Cell Death Research, Basic Technology Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center, Kitakasai 1-16-13, Edogawa-ku, Tokyo 134-8630, Japan. fax: 81-3-5696-8336
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Abstract

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.

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