Sphingolipid Signaling

National Institute Of Mental Health

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Abstract

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that regulates many vital biological processes, including cell growth, death, and differentiation. S1P has been shown to play important roles in normal and patho-physiological processes, including cancer, asthma, allergic responses, hearing, and development of the cardiovascular and nervous systems. In a continuing and highly successful collaboration with Dr. Sarah Spiegel at Virginia Commonwealth University School of Medicine, we are elucidating the mechanisms by which S1P is produced by two sphingosine kinases (SphK1 and SphK2), how its levels are regulated, and how it mediates such diverse actions. S1P is a ligand for five specific G protein-coupled receptors (named S1Psub(1-5)) that regulate many vital cellular processes and account for the pleiotropic effects of S1P. In fact, no cell in the body has been found that does not express as least one S1P receptor. Although they were long considered to be merely structural components of membranes, in the recent decades it has become apparent that sphingolipids have other important functions. More recently, S1P and its precursors, sphingosine and ceramide, have been implicated in the regulation of many aspects of neuronal proliferation, differentiation, survival and apoptosis. We have been developing specific SphK1 inhibitors as potential therapeutic agents. We previously reported that a specific isotype inhibitor of SphK1 that we called SK1-I decreased growth and survival of human leukemia cell lines and primary leukemia cells from patients, and markedly reduced growth of xenograft tumors grown from human leukemia cells implanted in mice. Elevated levels of SphK1, but not SphK2, were correlated with a shorter survival prognosis for patients with glioblastoma multiforme. Chronic inflammation and inflammatory cytokines have recently been implicated in the development and progression of various types of cancer. In the brain, neuroinflammatory cytokines affect the growth and differentiation of both normal and malignant glial cells, with interleukin 1 (IL-1) shown to be secreted by the majority of glioblastoma cells. S1P induces invasion of glioblastoma cells. In this study, we showed that the expression of IL-1 correlates with the expression of SphK1 in glioblastoma cells, and neutralizing anti-IL-1 antibodies inhibit both the growth and invasion of glioblastoma cells. Furthermore, IL-1 up-regulates SphK1 mRNA levels, protein expression, and activity in both primary human astrocytes and various glioblastoma cell lines;however, it does not affect SphK2 expression. In summary, our results suggest that SphK1 expression is transcriptionally regulated by IL-1 in glioblastoma cells, and this pathway may be important in regulating survival and invasiveness of glioblastoma cells. In preliminary studies, we have also found that treating mice with the SphK1 inhibitor SK1-I inhibited glioblastoma tumor growth and enhanced survival. In an invited review, we summarized the data to date on the roles of S1P and the kinases that produce it as critical regulators of numerous fundamental biological processes important for health and disease. Activation of SphKs by a variety of agonists increases intracellular S1P, which in turn can be secreted out of the cell and bind to and signal through S1P receptors (S1PRs) in an autocrine and/or paracrine manner. We suggest that this "inside-out" signaling by S1P may play a role in many human diseases. We focussed this review mainly on recent reports showing how SphKs are activated and how S1P reaches its receptors, the role of SphKs and S1P in regulating sphingolipid homeostasis, and the potential importance of the SphK/S1P axis as a therapeutic target in human diseases. We previously found that SphK1 was important for cell growth and survival and SphK2 seemed to inhibit proliferation and promote cell death. SphK1 and SphK2 have different cellular localizations and have opposing roles in the regulation of sphingolipid metabolism suggesting that the location of S1P production in the cell dictates its functions. In a paper that will be published September 4, 2009 in Science, we report the important discovery that cell nuclei contain S1P that is produced there by nuclear localized SphK2 and that SphK2 and S1P are important endogenous regulators of gene transcription. We found that S1P was an endogenous inhibitor of histone deacetylases (HDACs), enzymes that regulate chromatin structure and gene expression and thus HDACs are the first identified intracellular targets of S1P. Our data reveal a new paradigm of S1P signaling produced by nuclear sphingolipid metabolism, suggesting an important function for SphK2 in the nucleus. HDACs have emerged as key targets to reverse aberrant epigenetic changes associated with human diseases, such as cancer. S1P may therefore influence the delicate balance and dynamic turnover of histone acetylation and the transcription of target genes, linking them to epigenetic regulation in response to environmental signals.