Activation of Fas receptor modulates cytochrome P450 3A4 expression in human colon carcinoma cells

Abstract

The Fas (CD95, APO-1) receptor is a transmembrane cell surface receptor that mediates apoptosis in many cell types when bound by the Fas ligand or cross-linked by agonistic anti-Fas antibodies. Fas activation engages a potent and rapid signaling mechanism in a variety of cell types. In the present study, we have investigated the effects of Fas receptor activation on CYP3A4 expression in human colon carcinoma HT-29 cells. The intracellular ceramide levels were significantly enhanced by the treatment with the anti-Fas antibodies and both CYP3A4 protein and mRNA expression was suppressed by Fas activation in a dose-dependent manner. Immunoblot analyses showed that the expression of iNOS protein was significantly stimulated by an anti-Fas antibody treatment in HT-29 cells. Fas receptor activation also increased the generation of reactive oxygen species, and N-acetylcysteine, a well-known antioxidant, could block Fas-mediated NOS induction. These results show that the Fas receptor-mediated signaling pathways modulate CYP3A4 expression in human colon cancer cells. Overall, iNOS induction and P450 3A4 suppression by Fas activation may cause toxic cellular damage in gastrointestinal tissues. (C) 2003 Elsevier Ireland Ltd. All fights reserved.