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Hepatocyte growth factor induces Mcl‐1 in primary human hepatocytes and inhibits CD95‐mediated apoptosis via Akt
Author(s) -
SchulzeBergkamen Henning,
Brenner Dirk,
Krueger Andreas,
Suess Dorothee,
Fas Stefanie C.,
Frey Christian R.,
Dax Andreas,
Zink Dorothea,
Büchler Peter,
Müller Martina,
Krammer Peter H.
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20138
Subject(s) - hepatocyte growth factor , protein kinase b , pi3k/akt/mtor pathway , mapk/erk pathway , cancer research , signal transduction , stat3 , apoptosis , microbiology and biotechnology , kinase , biology , ly294002 , stat protein , chemistry , biochemistry , receptor
CD95 (APO‐1/Fas)‐mediated apoptosis of hepatocytes plays a central role in the pathophysiology of various human liver diseases. Hepatocyte growth factor (HGF) was shown to exert antiapoptotic functions in rodent hepatocytes. We previously showed that primary human hepatocytes (PHH) are a valuable tool for the investigation of apoptotic processes in liver cells. In this study, we analyzed the influence of HGF on CD95‐mediated apoptosis of PHH and its molecular determinants. HGF significantly inhibited CD95‐mediated apoptosis of PHH as well as cleavage of caspase‐8 and poly (ADP‐ribose)polymerase. HGF transcriptionally induced the expression of the anti‐apoptotic Bcl‐2 family member myeloid cell leukemia‐1 (Mcl‐1). In contrary, HGF did not alter the expression levels of Bcl‐2 or Bcl‐x L . HGF activated survival pathways such as the phosphatidylinositol‐3 kinase (PI3K)/Akt pathway, the mitogen‐activated protein kinase/extracellular signal‐regulated kinase (ERK) kinase/ERK and the signal transducer and activator of transcription 3 (STAT3) pathway. Notably, HGF triggered serine 727 —but not tyrosine 705 —phosphorylation of STAT3. Pretreatment of PHH with the PI3K inhibitor LY294002 as well as adenoviral transduction of dominant negative Akt1 prevented HGF‐mediated Mcl‐1 induction and reversed the antiapoptotic effects of HGF. In conclusion, HGF confers survival of PHH by activation of the PI3K/Akt pathway. PI3K/Akt activation by HGF results in the induction of antiapoptotic proteins such as Mcl‐1. Thus, application of HGF may be a therapeutic approach to prevent CD95‐mediated hepatocellular damage in human liver diseases. (H EPATOLOGY 2004;39:645–654.)