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-mediate d cell death, which is one of the effector mechanisms in the host's anti-tu mor response; however, this resistance can be abolished by interferon-gamma (IFN-gamma). IFN-gamma may sensitize Fas-mediated cell death in several wa ys, but the exact mechanism in HCCs is uncertain. In this study, we thoroug hly 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. W e also investigated the effect of IFN-gamma on the expression of various ap optosis-related genes such. as the Fas/TNF-related genes, the bcl-2 family, and the caspase family of genes. Although most cell lines showed considera ble constitutive expression of Fas, all tested cell lines resisted Fas-medi ated cell death without IFN-gamma. When cells were pretreated with IFN-gamm a, only three cell lines were made significantly susceptible to Fas-mediate d cell death (SNU-354, SNU-387 and SNU-423); the other 10 cell lines were n ot affected. IFN-gamma increased the mRNA expression of Fas, TRAIL and casp ase-1, and surface Fas was also increased. The strongly sensitized cell lin es (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 I FN-gamma makes HCC cells susceptible to Fas-mediated cell death through a m arked up-regulation of surface Fas in some HCC cells.