Phytosphingosine and C2‐phytoceramide induce cell death and inhibit carbachol‐stimulated phospholipase D activation in Chinese hamster ovary cells expressing the Caenorhabditis elegans muscarinic acetylcholine receptor

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Abstract
Sphingolipid metabolites, such as sphingosine and ceramide, are known to play important roles in cell proliferation, differentiation and apoptosis, but the physiological roles of phytosphingosine (PHS) and phytoceramide (PHC) are poorly understood. In this study we investigated the effects of PHS, C2-PHC (N-acetylPHS) and C6-PHC (N-hexanoylPHS) on cell growth and intracellular signalling enzymes. Treatment of Chinese hamster ovary (CHO) cells with PHS, C2-PHC or C6-PHC resulted in cell death in a time- and dose-dependent manner. C2-PHC induced internucleosomal DNA fragmentation, whereas PHS or C6-PHC had little if any effect on DNA fragmentation under the same experimental conditions. Both PHS and C2-PHC inhibited carbachol-induced activation of phospholipase D (PLD), but not of phospholipase C (PLC), in CHO cells expressing the Caenorhabditis elegans muscarinic acetylcholine receptor (mAChR). On the other hand, no significant effect of C6-PHC on PLD or PLC was observed. Our results show that PHS and C2-PHC exert strong cytotoxic effects on CHO cells and modulate the mAChR-mediated signal transduction pathway.