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Vol. 62, Issue 5, 1068-1075, November 2002

Inhibition of CTP:Phosphocholine Cytidylyltransferase by C2-Ceramide and Its Relationship to Apoptosis

Belén Ramos, Mohammed El Mouedden, Enrique Claro, and Suzanne Jackowski

Departamento de Fisiología, Universidad de Extremadura, Cáceres, Spain (B.R.); Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, Tennessee (M.E.M., S.J.); and Institut de Neurociències and Departamento de Bioquimica, Universitat Autònoma de Barcelona, Barcelona, Spain (E.C.).

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.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics