Effect of interferon-gamma on the susceptibility to Fas (CD95/APO-1)-mediated cell death in human hepatoma cells.
Many tumors, including hepatocellular carcinomas (HCCs), resist Fas-mediated cell death, which is one of the effector mechanisms in the host's anti-tumor response; however, this resistance can be abolished by interferon-gamma (IFN-gamma). IFN-gamma may sensitize Fas-mediated cell death in several ways, but the exact mechanism in HCCs is uncertain. In this study, we thoroughly investigated the effect of IFN-gamma on the susceptibility of one human normal liver cell line and 12 HCC cell lines to Fas-mediated cell death. We also investigated the effect of IFN-gamma on the expression of various apoptosis-related genes such as the Fas/TNF-related genes, the bcl-2 family, and the caspase family of genes. Although most cell lines showed considerable constitutive expression of Fas, all tested cell lines resisted Fas-mediated cell death without IFN-gamma. When cells were pretreated with IFN-gamma, only three cell lines were made significantly susceptible to Fas-mediated cell death (SNU-354, SNU-387 and SNU-423); the other 10 cell lines were not affected. IFN-gamma increased the mRNA expression of Fas, TRAIL and caspase-1, and surface Fas was also increased. The strongly sensitized cell lines (SNU-354, SNU-387 and SNU-423) showed a particularly potent increment in surface Fas after IFN-gamma treatment (increase in surface Fas > 1.7-fold). This result enabled us to conclude that a potent increment of surface Fas expression is a major sensitizing mechanism of IFN-gamma. We conclude that IFN-gamma cannot play a sensitizing role in most HCC cell lines and that IFN-gamma makes HCC cells susceptible to Fas-mediated cell death through a marked up-regulation of surface Fas in some HCC cells.
Shin
E C
EC
Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, CPO Box 8044, Seoul, 120-752 Korea.
Shin
W C
WC
Choi
Y
Y
Kim
H
H
Park
J H
JH
Kim
S J
SJ
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D020170:Caspase 1 / Q000235:genetics; D019254:Genes, bcl-2; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D012333:RNA, Messenger; D019014:fas Receptor; D007371:Interferon-gamma; D020170:Caspase 1