title: Mcl-1 is an anti-apoptotic factor for human hepatocellular carcinoma.
abstract: Defects in apoptosis signaling in hepatocytes contribute to tumorigenesis in hepatocellular carcinoma (HCC). In addition, treatment with chemotherapeutic drugs is often ineffective in HCC patients due to the apoptosis resistance of cancer cells. Anti-apoptotic members of the Bcl-2 family, including myeloid cell leukemia-1 (Mcl-1), which regulate intrinsic apoptosis induction at the mito-chondrial level, are often overexpressed in human cancer, and are implicated with disease grade and prognosis. Yet, little is known about the role of Mcl-1 in HCC. In this study, we analyzed the relevance of Mcl-1 expression for the apop-tosis resistance of human HCC. Mcl-1 protein expression was considerably enhanced in human HCC tissue compared to adjacent non-tumor tissue. In addition, Mcl-1 was prominently expressed in various HCC cell lines. Mcl-1 basal expression is dependent on a functional phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway; treatment of the cells with a specific PI3 kinase inhibitor led to both decreased Mcl-1 expression and a sensitization towards chemotherapeutic drug-induced apoptosis. Furthermore, the hepatocyte growth factor and epidermal growth factor induced Mcl-1 expression in an Akt- and ERK-dependent manner. Finally, specific upregulation of Mcl-1 in HCC cells inhibited chemotherapeutic drug-induced apoptosis. Our data suggest that Mcl-1 is an important factor for the apoptosis resistance of human HCC, and constitutes an interesting target for HCC therapy.
authors.affiliation: I. Department of Medicine, Johannes Gutenberg University Mainz, 55101 Mainz, Germany.
authors.forename: Binje
authors.initials: B
authors.lastname: Fleischer
authors.forename: Henning
authors.initials: H
authors.lastname: Schulze-Bergkamen
authors.forename: Marcus
authors.initials: M
authors.lastname: Schuchmann
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Stefan
authors.initials: S
authors.lastname: Biesterfeld
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000503:physiopathology*; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt