PT  - JOURNAL ARTICLE
AU  - Belén Ramos
AU  - Mohammed El Mouedden
AU  - Enrique Claro
AU  - Suzanne Jackowski
TI  - Inhibition of CTP:Phosphocholine Cytidylyltransferase by  C<sub>2</sub>-Ceramide and Its Relationship to Apoptosis
AID  - 10.1124/mol.62.5.1068
DP  - 2002 Nov 01
TA  - Molecular Pharmacology
PG  - 1068--1075
VI  - 62
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/62/5/1068.short
4100  - http://molpharm.aspetjournals.org/content/62/5/1068.full
SO  - Mol Pharmacol2002 Nov 01; 62
AB  - 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.