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.
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.
Suzuki
A
A
Project for the Cell Death Research, Basic Technology Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center, Tokyo, Japan. LEB003783@nifty.ne.jp
Hayashida
M
M
Kawano
H
H
Sugimoto
K
K
Nakano
T
T
Shiraki
K
K
D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D019014:fas Receptor / Q000502:physiology*
D017228:Hepatocyte Growth Factor; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; C494918:AKT1 protein, human; C494929:PTEN protein, human