Sphingolipid Signaling

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that regulates many vital biological processes, including cell growth, death, and differentiation. 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 S1P{sub(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.[unreadable] 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. More recently, we discovered that S1P regulates levels of its precursor, ceramide, in the endoplasmic reticulum (ER) and that the ceramide levels in turn influence the anterograde membrane transport of both lipids and proteins from the ER to the Golgi apparatus and then to the cell surface.[unreadable] In a recent study of the role of SphK1, the enzyme that produces S1P, in breast cancer cells, we found that EGF, an important growth factor for breast cancer progression, activated and translocated SphK1 to plasma membrane. This was required for EGF-directed motility of breast cancer cells. Moreover, downregulation of SphK1 reduced EGF- and serum-stimulated growth and enhanced their sensitivity to doxorubicin, a potent chemotherapeutic agent. Our results suggest that SphK1 may be critical for growth, metastasis and chemoresistance of human breast cancers. [unreadable] Because S1P receptors and the CB1 cannabinoid receptor are similar in sequence, have similar expression patterns in specific brain regions, and S1P levels are high in the CNS, we investigated the interactions of S1P with CB1 and CB2. It was also of interest to examine the interactions of CB1 with the potent immunosuppressant drug FTY720 that is in clinical trials for multiple sclerosis, a sphingosine analogue that is phosphorylated in vivo to a S1P mimetic that binds to 4 of the 5 S1P receptors and accumulates to high levels in the CNS. Interestingly, while neither S1P nor FTY720-P were very weak cannabinoid ligands, we discovered that their precursors, sphingosine and FTY720, are ligands for CB1 but not CB2. Our data suggest that CB1 might be a novel target of FTY720 in the CNS and that the balance between sphingosine and S1P might influence the activity of endogenous cannabinoids.[unreadable] In a recent issue of Cancer Cell, it was demonstrated that a monoclonal antibody that binds S1P with extremely high affinity and specificity significantly slows tumor progression and associated angiogenesis in several animal models of various types of human cancer. In a commentary on this paper, we suggested that S1P not only affects tumor cells themselves, but also is permissive or required for the actions of tumor and host angiogenic factors, and thus may be a bona fide cancer target.[unreadable] We previously cloned a novel type of lipid kinase that phosphorylates monoacylglycerols (such as 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand) and diacylglycerols, to form LPA and PA, respectively, which regulate pivotal processes related to the pathogenesis of cancer. AGK (acylglycerol kinase) is highly expressed in prostate cancer cell lines and our review of the literature led us to suggest that AGK might be a critical player in the initiation and progression of prostate cancer. We discussed the evidence demonstrating that AGK amplifies EGF growth signaling pathways that play an important role in the pathophysiology of prostate cancer. Because LPA has long been implicated as an autocrine and paracrine growth stimulatory factor for prostate cancer cells, its production by AGK could be a new target for preventive or therapeutic measures.