Inhibition of CTP:phosphocholine cytidylyltransferase by C<inf>2</inf>-ceramide and its relationship to apoptosis

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

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1068-1075
JournalMolecular Pharmacology
Volume62
DOIs
Publication statusPublished - 1 Nov 2002

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