The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis.
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 (13)C,(15)N-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 IC(50) of 78.9 +/- 1.5 muM 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.
Schiffmann
Susanne
S
Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. susanne.schiffmann@med.uni-frankfurt.de
Sandner
Jessica
J
Schmidt
Ronald
R
Birod
Kerstin
K
Wobst
Ivonne
I
Schmidt
Helmut
H
Angioni
Carlo
C
Geisslinger
Gerd
G
Grösch
Sabine
S
D017209:Apoptosis; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008055:Lipids / Q000737:chemistry; D008954:Models, Biological; D008956:Models, Chemical; D011720:Pyrazoles / Q000494:pharmacology*; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D013107:Sphingolipids / Q000737:chemistry / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D008055:Lipids; D011720:Pyrazoles; D013107:Sphingolipids; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D051102:Serine C-Palmitoyltransferase; D000068579:Celecoxib