Functional absence of FADD in PLC/PRF/5 hepatoma cells: Possible involvement in the transformation to hepatoma in HBV-infected hepatocytes

The death receptor Fas transduces apoptotic death signaling upon stimulatio n by Fas ligand and plays a key role In viral hepatitis. When hepatitis-B v irus(HBV) infects hepatocytes, the Fas ligand/Fas system responds as the tr iggering machinery of hepatitis. However, some HBV-infected cells may circu mvent Fas-meditated apoptosis and transform to hepatoma cells, as do PLC/PR F/5 hepatoma cells, Therefore, in the present study, we used PLC/PRF/5 hepa toma cells to investigate this ability to avoid Fas-mediated apoptosis. Whe n the cells were treated with an agonistic Fas antibody, they showed resist ance to Fas-mediated apoptosis. In contrast, HepG2 cells of the same hepato ma line succumbed. Caspase 3 and 8, which are essential regulators for Fas- mediated cell death, were expressed in both hepatoma cell lines, but only H epG2 cells showed activation of the caspases. A comparison study of express ion of other death-associated factors between PLC/PRF/5 and HepG2 cells rev ealed no apparent differences. However, Far-Western blotting analysis using the Fas death domain (FDD) showed a significant difference. Molecular weig ht comparison and immunoblotting analysis revealed that PLC/PRF/5 cells lac k the FDD-associated protein FADD, In addition, FDD-injected HepG2 cells sh owed a resistance to Fas-mediated apoptosis, and PLC/PRF/5 cells acquired F as-sensitivity by FADD injection, Here, we propose that a functional absenc e of FADD is one of the pathways for the carcinogenesis of HBV-infected hep atocytes.