O

Ceramide

Fatty acids: C16-C30, mostly saturated, sometimes a-hydroxylated

-Glucose-Galactose-NeuAc-NeuAc Ganglioside GD3

FIGURE 25.1 Structure of sphingolipids.

inhibition, induction of senescence, cell death via apoptosis and necrosis, inhibition of migration and induction of differentiation. However, multiple other enzymes of the sphingolipid metabolism now have been identified as targets and, accordingly, other sphingolipids and sphingolipid metabolites have been implicated in the regulation of cell behavior. These include sphingosine, several gan-gliosides, glucosylceramide, lactosylceramide, ceramide-1-phosphate, and sphin-gosine-1-phosphate. The different metabolites may have opposing effects, such as sphingosine-1-phosphate, which in contrast to ceramides and sphingoid bases stimulates cell growth, increases the survival of cells, suppresses apoptosis, affects cell differentiation, and modulates cytoskeleton organization, adhesion, and cell motility.1015 The effects of metabolites such as octadecane-1,2-diol are also discussed.16 The differential activation of enzymes of sphingolipid metabolism, and the amount and species of bioactive sphingolipid metabolites — and their intracellular localization — are therefore crucial determinants of the cellular response and, thus, may be targets for regulation.

25.2.2 Sphingolipid Metabolism in Cancer Cells

Changes in the sphingolipid metabolism in cancer cells may generate "wrong" metabolites or cause the depletion of appropriate metabolites, and thereby create conditions that support unlimited cell growth and that prevent regulation by exogenous agents. Aberrant enzyme activity or expression that affects sphingolipid metabolism has been reported in several cancer systems. A reduced activity and expression of sphingomyelinases in colonocytes of carcinogen-treated rats17,18 and in human tumors,19 may result in the failure to generate ceramide in response to extracellular stimuli, and protect cells from undergoing apoptosis. This is also the underlying mechanism of the resistance of some tumor cells to y-irradiation20,21 and chemotherapeutic agents.22,23 An overexpression of acid ceramidase in tumor cells has been shown to protect against TNF-a-induced apoptosis,24 removing cytotoxic ceramide and releasing sphingosine as substrate for sphingosine kinase. An increase in sphingosine kinase activity with the subsequent accumulation of sphingosine-1-phosphate has been correlated with hyper-proliferation, transformation, and development of a malignant tumor phenotype.25 Ovarian tumors not only show a significant elevation of sphingosine-1-phosphate in tumor tissue itself,26 but also secrete sphingosine-1-phosphate into ascites fluid, affecting cell dissemination and attachment on distal sites.27 Thus, the inhibition of sphingosine kinase and suppression of the generation of mitotic metabolites may be effective in these tumor types, and clinical trials testing this hypothesis are already ongoing.

Another pathway in cancer cells to reduce ceramide accumulation is to upregulate synthesis of complex sphingolipids, glucosylceramide, and, to a lesser extent, sphingomyelin. This has been shown to be a critical event in some mul-tidrug-resistant cells,28 and inhibition of glucosylceramide synthase activity, the enzyme responsible for the transfer of glucose to the ceramide moiety, has been the subject of extended investigations; drugs inhibiting this enzyme are being tested in patients. However, more recent reports demonstrated that transfection of melanoma cells with a functioning glucosylceramide synthase did not reverse the multidrug-resistant phenotype.29 Furthermore, the use of more selective glu-cosylceramide synthase inhibitors did not reverse multidrug resistance, and the authors hypothesize that the previously used inhibitor PDMP may have effects in addition to inhibition of glucosylceramide synthase that affect multidrug resistance.30 Given the importance of targeting specific enzymes in cancer cells to avoid side effects, the role of glucosylceramide synthase in the chemoresistance of cancer cells clearly needs to be clarified.

The changes in the activity of enzymes in sphingolipid metabolism can modify the intracellular composition of bioactive sphingolipids. The levels of ceramide are reportedly reduced in head and neck squamous cell carcinomas, (specifically C18-ceramide31), colon cancer,32 larynx carcinoma,33 and astrocyto-mas.34 These low levels were associated with unlimited proliferation, resistance to apoptosis, and a poor outcome for the patients. A low ceramide content was also associated with chemoresistance of leukemia cells in vitro and in vivo.35 A decrease in lactosylceramide, but elevation of glucosylceramide, galactosylcera-mide, and gangliosides were observed in tumor cells.293436 37 Reversal of these changes lowered the resistance of cells to treatment38,39 and enhanced vincristine, doxorubicin, and taxol toxicity35 40-42 and the efficiency of radiation treatment.43 Decreased ganglioside levels suppressed tumor formation and metastasis in a syngeneic melanoma model.44 In contrast, other laboratories found increases in the ceramide and dihydroceramide (which lacks the 4,5-trans double bond required for its biological activity) content in sarcomas, melanomas, and Lewis lung carcinomas45 and transformed fibroblasts,46 possibly a requisite for the survival of these tumors.

The changes in the sphingolipid composition in cancer cells may be used for diagnosis purposes and for treatment decisions and prediction of drug efficacy.

For example, human glioma cell lines (LN18, LN229, LN319, and T98G) were analyzed for their sphingolipid composition using a combination of liquid chro-matography and tandem mass spectrometry. Several cell lines contained elevated sphingosine-1-phosphate levels47 and may therefore be candidates for treatment with sphingosine kinase inhibitors.

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