Retinoic acid and vitamin E modulate expression and release of CD178 in carcinoma cells: Consequences for induction of apoptosis in CD95-sensitive cells

CD178 (CD95-ligand) is expressed on several tumor cells and likely influenc es the interaction of the tumor with the host immune system. However, littl e is known about the mechanisms that regulate its expression on the cell su rface. We have evaluated the ability of various compounds and cytokines to regulate cell surface expression and release of soluble CD178 in various ca rcinoma cell lines. Vitamin E succinate (VES) and retinoic acid (RA) were f ound to reduce CD178 surface expression, whereas interferon-gamma stimulate d a slight upregulation. At 48 h, the regulation of surface CD178 by VES an d RA arose from a small decrease in CD178 mRNA and to a greater extent due to an increase in the release of soluble CD178; the latter was blocked by a ddition of a metalloproteinase inhibitor. Accordingly, VES and RA treatment diminished the ability of tumor cells to kill CD95-sensitive cells and thi s effect was markedly reduced by the presence of a metalloproteinase inhibi tor. Our results indicate that, in vitro, CD178 expression on the cell surf ace of tumor cells can be regulated by agents that alter both expression an d release of the ligand. In vivo, such treatments may play an important rol e in the outcome of tumor sensitivity or resistance to host immune mechanis ms. (C) 2001 Academic Press.