Activation of Fas receptor modulates cytochrome P450 3A4 expression in human colon carcinoma cells.
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 iNOS 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.
Chun
Young-Jin
YJ
College of Pharmacy, Chung-Ang University, 221 Huksuk-Dong, Dongjak-Ku, Seoul 156-756, South Korea. yjchun@cau.ac.kr
Park
Sungsik
S
Yang
Soon Ae
SA
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002518:Ceramides / Q000096:biosynthesis; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D002518:Ceramides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019014:fas Receptor; D003577:Cytochrome P-450 Enzyme System; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human