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Papers In Press, published online ahead of print January 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800122-JLR200

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Journal of Lipid Research, Vol. 50, 32-40, January 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis

Susanne Schiffmann¹, Jessica Sandner, Ronald Schmidt, Kerstin Birod, Ivonne Wobst, Helmut Schmidt, Carlo Angioni, Gerd Geisslinger and Sabine Grösch

Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of five figures.

Published, JLR Papers in Press, 18 August 2008.

This work was supported by the Deutsche Forschungsgemeinschaft Forschergruppe FOG 784/TP5 (GR2011/2-1).

¹ To whom correspondence should be addressed. e-mail: susanne.schiffmann{at}med.uni-frankfurt.de

Sphingolipids such as ceramides (Cers) play important roles in cell proliferation, apoptosis, and cell cycle regulation. An increased Cer level is linked to the cytotoxic effects of several chemotherapeutics. Various selective cyclooxygenase-2 (COX-2) inhibitors induce anti-proliferative effects in tumor cells. We addressed the possible interaction of the selective COX-2 inhibitors, coxibs, with the sphingolipid pathway as an explanation of their anti-proliferative effects. Sphingolipids were measured using liquid chromatography tandem mass spectrometry. Treatment of various cancer cell lines with celecoxib significantly increased sphinganine, C_16:0-, C_24:0-, C_24:1-dihydroceramide (dhCer) and led to a depletion of C_24:0-, C_24:1-Cer in a time- and concentration-dependent manner, whereas other coxibs had no effect. Using ¹³C,¹⁵N-labeled L-serine, we demonstrated that the augmented dhCers after celecoxib treatment originate from de novo synthesis. Celecoxib inhibited the dihydroceramide desaturase (DEGS) in vivo with an IC₅₀ of 78.9 ± 1.5 µM and increased total Cer level about 2-fold, indicating an activation of sphingolipid biosynthesis. Interestingly, inhibition of the sphingolipid biosynthesis by specific inhibitors of L-serine palmitoyltransferase diminished the anti-proliferative potency of celecoxib. In conclusion, induction of de novo synthesis of sphingolipids and inhibition of DEGS contribute to the anti-proliferative effects of celecoxib.

Supplementary key words cancer • cyclooxygenase-2 • apoptosis • dihydroceramide desaturase • ceramide • dihydroceramide

Abbreviations: Cer, ceramide; CerS, (dihydro)ceramide synthase; C8-CPPC, C8-cyclopropenylceramide; COX-2, cyclooxygenase-2; DEGS, dihydroceramide desaturase; dhCer, dihydroceramide; dhSph, sphinganine; dhSph1P, sphinganine-1-phosphate; FB1, fumonisin B1; FCS, fetal calf serum; GCS, glucosylceramide synthase; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography tandem mass spectrometry; SMase, sphingomyelinase; Sph, sphingosine; Sph1P, sphingosine-1-phosphate; Sph1PP, sphingosine-1-phosphate phosphatase; L-SPT, L-serine palmitoyltransferase

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