TY - JOUR T1 - Inhibition of CTP:Phosphocholine Cytidylyltransferase by C<sub>2</sub>-Ceramide and Its Relationship to Apoptosis JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1068 LP - 1075 DO - 10.1124/mol.62.5.1068 VL - 62 IS - 5 AU - Belén Ramos AU - Mohammed El Mouedden AU - Enrique Claro AU - Suzanne Jackowski Y1 - 2002/11/01 UR - http://molpharm.aspetjournals.org/content/62/5/1068.abstract N2 - Apoptosis induced by antitumor phospholipid analogs takes place after the inhibition of the CTP:phosphocholine cytidylyltransferase (CCT; EC 2.7.7.15) catalyzed step of phosphatidylcholine (PtdCho) biosynthesis. Exposure of cells to synthetic short-chain ceramide analogs also triggers apoptosis concomitant with decreased PtdCho biosynthesis, and the present study was undertaken to ascertain whether C2-ceramide inhibition of PtdCho synthesis is direct or secondary to other ceramide-mediated cellular responses. The exposure of COS-7 cells to either C2-ceramide, ET-18-OCH3, or farnesol resulted in time- and dose-dependent apoptotic cell death. Cells treated with C2-ceramide or ET-18-OCH3 selectively and immediately accumulated phosphocholine, whereas CDP-choline increased with farnesol treatment. In vitro assays of CCT activity demonstrated that C2-ceramide directly inhibited CCT. Comparison of different N-linked sphingosine derivatives suggests an inverse relationship between the length of the N-linked carbon chain and the derivatives ability to trigger apoptosis and inhibit CCT. Taken together, our results suggest CCT as a primary target for C2-ceramide inhibition that accounts for its cytotoxic effects. ER -