Dimethylsphingosine and FTY720 inhibit the SK1 form but activate the SK2 form of sphingosine kinase from rat heart

Vessey, Donald A.; Kelley, Michael S. P.; Li, Luyi; Tao, Rong; Karliner, Joel S.

doi:10.1002/jbt.20193

Cited by 70 publications

(84 citation statements)

References 29 publications

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“…FTY720 has been previously reported to inhibit SphK1 in situ (35). In our study we show for the first time that FTY720 has a capacity to inhibit SphK1 enzymatic activity in vitro (Fig.…”

Section: Discussionsupporting

confidence: 67%

“…FTY720 is a sphingosine analogue and was previously shown to inhibit enzymatic activity of recombinant SphK1 (35). Here we report that FTY720 induced a rapid inhibition of SphK1 enzymatic activity in PC-3 and DU145 cells (-28 ± 5% and -40 ± 5% in PC-3 and DU145 cells, respectively, at 6 hours; Fig.…”

Section: Sphingosine Analogue Fty720 Induces Apoptosis In Prostate Camentioning

confidence: 53%

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FTY720 (Fingolimod) Sensitizes Prostate Cancer Cells to Radiotherapy by Inhibition of Sphingosine Kinase-1

et al. 2010

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Radiotherapy is widely used as a radical treatment for prostate cancer, but curative treatments are elusive for poorly differentiated tumors where survival is just 15% at 15 years. Dose escalation improves local response rates but is limited by tolerance in normal tissues. A sphingosine analogue, FTY720 (fingolimod), a drug currently in phase III studies for treatment of multiple sclerosis, has been found to be a potent apoptosis inducer in prostate cancer cells. Using in vitro and in vivo approaches, we analyzed the impact of FTY720 on sphingolipid metabolism in hormone-refractory metastatic prostate cancer cells and evaluated its potential as a radiosensitizer on cell lines and prostate tumor xenografts. In prostate cancer cell lines, FTY720 acted as a sphingosine kinase 1 (SphK1) inhibitor that induced prostate cancer cell apoptosis in a manner independent of sphingosine-1-phosphate receptors. In contrast, γ irradiation did not affect SphK1 activity in prostate cancer cells yet synergized with FTY720 to inhibit SphK1. In mice bearing orthotopic or s.c. prostate cancer tumors, we show that FTY720 dramatically increased radiotherapeutic sensitivity, reducing tumor growth and metastasis without toxic side effects. Our findings suggest that low, well-tolerated doses of FTY720 could offer significant improvement to the clinical treatment of prostate cancer. Cancer Res; 70(21); 8651-61. ©2010 AACR.

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“…FTY720 has been previously reported to inhibit SphK1 in situ (35). In our study we show for the first time that FTY720 has a capacity to inhibit SphK1 enzymatic activity in vitro (Fig.…”

Section: Discussionsupporting

confidence: 67%

Section: Sphingosine Analogue Fty720 Induces Apoptosis In Prostate Camentioning

confidence: 53%

FTY720 (Fingolimod) Sensitizes Prostate Cancer Cells to Radiotherapy by Inhibition of Sphingosine Kinase-1

et al. 2010

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“…Furthermore, the water-soluble sphingosine analog FTY720 has been shown to induce caspase-independent cell death through the downregulation of nutrient transporters and induction of autophagy ( 144,145 ). However, treatment with FTY720, which is reported to inhibit S1P lysase ( 146 ), SK1 ( 147 ), and CerS ( 148,149 ), induced such effects independent of ceramide production and S1P receptors ( 145 ), suggesting a mechanism that is distinct from ceramide and the SK inhibitors described above.…”

Section: Sphingosinementioning

confidence: 97%

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Young

Kester

Wang

2013

Journal of Lipid Research

293

274

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decades ago, pioneering work by Hannun et al. and Kolesnick et al. established the foundation for the bioactive nature of sphingolipids by demonstrating the inhibition of protein kinase C (PKC) by sphingosine and the stimulation of a ceramide-activated protein kinase in response to tumor necrosis factor (TNF)-␣ , respectively ( 1, 2 ). Sphingolipids have since been recognized as critical activators or inhibitors of various protein kinases and phosphatases, receptors, and ion transporters ( 3 ). Moreover, sphingolipids have been identifi ed as key regulators of a vast number of cellular processes, including cell growth, adhesion, migration, senescence, apoptosis, and most recently, autophagy ( 3, 4 ).Much of the investigation into sphingolipid signaling has focused on the disparate nature of ceramide and sphingosine-1-phosphate (S1P). Ceramide is typically associated with growth arrest and apoptosis, while S1P promotes cell proliferation and survival. The opposing nature and dynamic balance of intracellular ceramide and S1P, termed the "sphingolipid rheostat," has been proposed to determine cell fate ( 5 ). However, emerging evidence and extensive characterization of the sphingolipid metabolic network suggests that this two-dimensional model does not adequately refl ect sphingolipid signaling and function within the cell. In addition to ceramide and S1P, other sphingolipid metabolites, such as sphingosine, dihydroceramide, and gangliosides, have been implicated in the regulation of apoptosis and macroautophagy (hereafter referred to as autophagy). Although autophagy is typically considered to be a cytoprotective mechanism for the suppression of apoptosis, recent evidence indicates that autophagy can also promote cell death ( 6 ). Due to the differential regulation of apoptosis and autophagy by sphingolipid metabolites, the sphingolipid network has emerged as a novel molecular switch between the apoptotic and autophagic Abstract Apoptosis and autophagy are two evolutionarily conserved processes that maintain homeostasis during stress. Although the two pathways utilize fundamentally distinct machinery, apoptosis and autophagy are highly interconnected and share many key regulators. The crosstalk between apoptosis and autophagy is complex, as autophagy can function to promote cell survival or cell death under various cellular conditions. The molecular mechanisms of crosstalk are beginning to be elucidated and have critical implications for the treatment of various diseases, such as cancer. Sphingolipids are a class of bioactive lipids that mediate many key cellular processes, including apoptosis and autophagy. By targeting several of the shared regulators, sphingolipid metabolites differentially regulate the induction of apoptosis and autophagy. Importantly, individual sphingolipid species appear to "switch" autophagy toward cell survival (e.g., sphingosine-1-phosphate) or cell death (e.g., ceramide, gangliosides). This review assesses the current understanding of sphingolipid-induced apoptosis and autophagy to addr...

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“…16 To date, a number of molecular targets have been suggested for the unphosphorylated form of FTY720, including cytosolic phospholipase A2, 17 protein phosphatase 2a (PP2a), 18 protein kinase Cδ, 14 ceramide synthase 19 and sphingosine kinase 1 (SphK1). 20 These downstream targets appear to be associated with the ability of FTY720 to suppress cell growth and/or induce cell death. first examined the cytotoxic effect of FTY720 on a panel of randomly collected human ovarian cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

FTY720 induces necrotic cell death and autophagy in ovarian cancer cells: A protective role of autophagy

Zhang

Wadham³

et al. 2010

Autophagy

108

121

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Dimethylsphingosine and FTY720 inhibit the SK1 form but activate the SK2 form of sphingosine kinase from rat heart

Cited by 70 publications

References 29 publications

FTY720 (Fingolimod) Sensitizes Prostate Cancer Cells to Radiotherapy by Inhibition of Sphingosine Kinase-1

FTY720 (Fingolimod) Sensitizes Prostate Cancer Cells to Radiotherapy by Inhibition of Sphingosine Kinase-1

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

FTY720 induces necrotic cell death and autophagy in ovarian cancer cells: A protective role of autophagy

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