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A more recent version of this article appeared on January 1, 2004

Papers In Press, published online ahead of print September 16, 2003
J. Lipid Res., doi:10.1194/jlr.M300300-JLR200
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Submitted on July 3, 2003
Revised on September 2, 2003
Accepted on September 8, 2003

The role of de novo ceramide synthesis in the mechanism of action of the tricyclic xanthate D609

Ryan J. Perry and Neale D. Ridgway

Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4H7

Corresponding Author: nridgway{at}dal.ca

The cytotoxic effects of several chemotherapeutic drugs have been linked to elevated de novo ceramide biosynthesis. However, the relationship between the intracellular site(s) of ceramide accumulation and cytotoxicity is poorly understood. Here we examined the relationship between the site of ceramide deposition and inhibition of protein translation and induction of apoptosis by the antitumor/antiviral xanthate, D609. In CHO-K1, HEK-293 and NIH-3T3 cells, D609 caused rapid (1-5 min) and sustained eIF2alpha phosphorylation followed by apoptosis after 24 h. Concurrently, D609 stimulated de novo ceramide synthesis and increased ceramide mass 2-fold by 2h in CHO-K1 cells. In D609-treated CHO-K1 cells, sphingomyelin synthesis was stimulated by brefeldin A and C5-DMB-ceramide transport to the Golgi apparatus was blocked, indicating ceramide accumulation in the endoplasmic reticulum. However, D609-mediated eIF2alpha phosphorylation, inhibition of protein synthesis and apoptosis in CHO-K1 cells was not attenuated by fumonisin B1 or L-cycloserine. Interestingly, short-chain ceramide promoted eIF2alpha phosphorylation and inhibited protein synthesis in CHO-K1 cells, indicating that the effectiveness of endogenous ceramide could be limited by access to signaling pathways. Thus expansion of the ER ceramide pool by D609 was not implicated in early (eIF2alpha phosphorylation) or late (apoptotic) cytotoxic events.


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