J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M300300-JLR200 on September 16, 2003

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Journal of Lipid Research, Vol. 45, 164-173, January 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

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

Ryan J. Perry and Neale D. Ridgway1

Departments of Pediatrics and Biochemistry and Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada

1 To whom correspondence should be addressed. e-mail: 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 Chinese hamster ovary (CHO)-K1, HEK-293, and NIH-3T3 cells, D609 caused rapid (1–5 min) and sustained eukaryotic initiation factor 2{alpha} (eIF2{alpha}) phosphorylation followed by apoptosis after 24 h. Concurrently, D609 stimulated de novo ceramide synthesis and increased ceramide mass 2-fold by 2 h 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 (ER). However, D609-mediated eIF2{alpha} phosphorylation, inhibition of protein synthesis, and apoptosis in CHO-K1 cells were not attenuated by fumonisin B1 or L-cycloserine. Interestingly, short-chain ceramide promoted eIF2{alpha} 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 (eIF2{alpha} phosphorylation) or late (apoptotic) cytotoxic events.

Abbreviations: BFA, brefeldin A; CHO, Chinese hamster ovary; DAG, diacylglycerol; eIF2{alpha}, eukaryotic initiation factor 2{alpha}; ER, endoplasmic reticulum; OSBP, oxysterol binding protein; PARP, poly(ADP-ribose) polymerase; PLC, phospholipase C; PKR, double-stranded RNA-dependent protein kinase; PtdCho, phosphatidylcholine; RAX, PKR activator X; SM, sphingomyelin; SPT, serine palmitoyltransferase

Supplementary key words eukaryotic initiation factor 2{alpha} • protein translation • fumonisin B1 • brefeldin A • endoplasmic reticulum export • serine palmitoyltransferase • apoptosis


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