Review
Sphingosine kinase, sphingosine-1-phosphate, and apoptosis

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Abstract

The sphingolipid metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) play an important role in the regulation of cell proliferation, survival, and cell death. Cer and Sph usually inhibit proliferation and promote apoptosis, while the further metabolite S1P stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determines cell fate. The relevance of this “sphingolipid rheostat” and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that Sph kinase (SphK), the enzyme that phosphorylates Sph to form S1P, is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic Cer and Sph.

Given the role of the sphingolipid rheostat in regulating growth and apoptosis, it is not surprising that sphingolipid metabolism is often found to be disregulated in cancer, a disease characterized by enhanced cell growth, diminished cell death, or both. Anticancer therapeutics targeting SphK are potentially clinically relevant. Indeed, inhibition of SphK has been shown to suppress gastric tumor growth [Cancer Res. 51 (1991) 1613] and conversely, overexpression of SphK increases tumorigenicity [Curr. Biol. 10 (2000) 1527]. Moreover, S1P has also been shown to regulate angiogenesis, or new blood vessel formation [Cell 99 (1999) 301], which is critical for tumor progression. Furthermore, there is intriguing new evidence that S1P can act in an autocrine and/or paracrine fashion [Science 291 (2001) 1800] to regulate blood vessel formation [J. Clin. Invest. 106 (2000) 951]. Thus, SphK may not only protect tumors from apoptosis, it may also increase their vascularization, further enhancing growth. The cytoprotective effects of SphK/S1P may also be important for clinical benefit, as S1P has been shown to protect oocytes from radiation-induced cell death in vivo [Nat. Med. 6 (2000) 1109]. Here we review the growing literature on the regulation of SphK and the role of SphK and its product, S1P, in apoptosis.

Section snippets

Sphingolipid metabolism

Sphingolipids are ubiquitous constituents of eukaryotic membranes characterized by the presence of an acylated sphingoid base, ceramide (Cer). Cer is deacylated by ceramidases, yielding a sphingoid base, the most common of these in mammals is sphingosine (Sph). In order for the sphingoid base to be catabolized, it must be phosphorylated on the 1-OH by Sph kinases (SphK). The product of this reaction, Sph-1-phosphate (S1P), is irreversibly degraded in the endoplasmic reticulum by S1P lyase to

SphK, the enzymes

The first mammalian SphK, murine or mSphK1, was cloned [29] based on tryptic peptides derived from highly purified rat SphK [30]. Two isoforms were cloned, termed mSphK1a and mSphK1b, that likely arose from alternative mRNA splicing and that differ by only a few amino acids at their amino-termini. Subsequently, human SphK1 was also cloned [31], [32], [33]. mSphK1 and hSphK1 have similar and broad adult tissue distributions, with mRNA being more highly expressed in brain, heart, lung, and

Activation of SphK

There is a rapidly growing list of agonists, especially growth and survival factors, that have been reported to increase SphK activity. These include ligands for G-protein coupled receptors (GPCR), including acetylcholine [41], [42], prosaposin [43], lysophosphatidic acid [44], formylmethionine peptide [45], and others [46], [47], [48]. Even S1P itself has been shown to activate SphK through a specific GPCR [49]. Agonists of growth factor receptor tyrosine kinases also mediate activation of

SphK and apoptosis

A number of studies demonstrate the pro-growth and anti-apoptotic effects of SphK. Perhaps the clearest of these involve the enforced expression of SphK1. Expression of SphK1 in NIH3T3, HEK293, and Jurkat T cells results in four- to eightfold increases in S1P levels but, somewhat paradoxically, almost 1000-fold increase in SphK activity measured in vitro [63]. The SphK1 overexpressing cells had decreased levels of Cer and Sph. Surprisingly, these cells still responded to PDGF like the vector

S1P and apoptosis

S1P was originally proposed to be an intracellular second messenger [83]. However, the demonstration that the endothelial differentiation gene-1 (EDG-1) family of GPCRs bind S1P has injected a note of caution into the interpretation of findings with exogenous S1P treatment of cells. Moreover, direct intracellular targets for S1P have yet to be identified. Complicating matters still further is the fact that S1P can be released from cells as an autocrine or paracrine signal [4]. Nonetheless,

S1P as an extracellular inhibitor of apoptosis

Although many studies support an intracellular site of action for the anti-apoptotic effects of S1P, there are some contradictory reports that propose an extracellular mechanism for S1P-induced cell survival and proliferation mediated by S1PRs. For example, nanomolar concentrations of S1P protected the T lymphoblastoma cell line Tsup-1 from Cer- and Fas-induced apoptosis as well as reduced levels of the pro-apoptotic protein Bax [104]. Transfection with antisense plasmids for S1P3/EDG-3 and S1P2

Acknowledgements

We thank the members of the Spiegel lab for their contributions to the studies that were quoted in this review. This work was supported by research grants from the National Institutes of Health (GM43880 and CA61774 to SS) and the Department of Defense (DAMD 17-02-1-0060 to SS) and postdoctoral fellowship (DAMD 7-02-1-0240 to MM). We apologize to those authors whose work could not be cited owing to space limitations.

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