Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5

Ikeda, Hitoshi; Satoh, Hiroaki; Yanase, Mikio; Inoue, Yukiko; Tomiya, Tomoaki; Arai, Masahiro; Tejima, Kazuaki; Nagashima, Kōzō; Maekawa, Hisato; Yahagi, Naohisa; Yatomi, Yutaka; Sakurada, Sotaro; Takuwa, Yoh; Ogata, Itsuro; Kimura, Satoshi; Fujiwara, Kenji

doi:10.1053/gast.2003.50049

Cited by 86 publications

(64 citation statements)

References 59 publications

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“…Considering G protein coupling properties of S1P 1 and S1P 2 receptors, S1P 1 may mediate the inhibition of adenylyl cyclase and S1P 2 may modulate phospholipase C activity in rat hepatocytes. Enhanced expression of S1P 2 in the primary cultured hepatocytes observed in our study has recently been observed the in vivo regenerating liver by Ikeda et al (26), confirming our assumption that the enhancement of the S1P activation of phospholipase C in the regenerating liver may also be due to increased expression of S1P 2 in vivo. Similar changes of S1P 2 expression were observed in other cell types: S1P 2 expression was down-regulated in F9 embryonic carcinoma cells when the cells were differentiated by the treatment of retinoic acid (27), and myogenic differentiation in C2C12 myoblasts, was accompanied with down-regulation of S1P 2 expression (28).…”

Section: Discussionsupporting

confidence: 92%

Enhancement of Sphingosine 1-Phosphate-Induced Phospholipase C Activation During G0-G1 Transition in Rat Hepatocytes

Tomura

Tobe

et al. 2004

J Pharmacol Sci

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Abstract. We previously reported that sphingosine 1-phosphate (S1P) induces inhibition of adenylyl cyclase and activation of phospholipase C via independent G protein-coupled receptors in adult rat hepatocytes. Although S1P activation of phospholipase C and subsequent increase of intracellular Ca 2+ concentration were enhanced during the primary culture of hepatocytes, S1P inhibition of adenylyl cyclase remained unchanged. Here, we addressed whether enhancement of S1P-induced actions is dependent on change of status from the differentiated (G 0 ) phase to proliferating (G 1 / S) phase in hepatocytes. By employing cell-density-dependency of the transition (G 0 -G 1 ) of hepatocytes in primary culture in vitro, it was found that the enhancement of phospholipase C activation by S1P was dependent on cell density and correlated to the G 0 -G 1 transition. The correlation was further confirmed in vivo by 70% hepatectomy as a proliferating hepatocytes model. Northern blot analysis suggested an enhanced expression of S1P 2 receptor in proliferating hepatocytes.

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Section: Discussionsupporting

confidence: 92%

Enhancement of Sphingosine 1-Phosphate-Induced Phospholipase C Activation During G0-G1 Transition in Rat Hepatocytes

Tomura

Tobe

et al. 2004

J Pharmacol Sci

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“…Additional experiments with isomers of LCL-30 have revealed S1P to be derived from endogenous sources and not from the breakdown of LCL-30 (Bielawska A, unpublished). S1P has been primarily regarded as a counter player of ceramide activity, although the intracellular compartmentalisation and the biological context (Ikeda et al, 2003) are important for its biological effects. Future experiments should take intracellular distribution of sphingosine kinase proteins into account.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice

Dahm¹,

Bielawska

Nocito³

et al. 2007

Br J Cancer

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The sphingolipid ceramide is intimately involved in the growth, differentiation, senescence, and death of normal and cancerous cells. Mitochondria are increasingly appreciated to play a key role in ceramide-induced cell death. Recent work showed the C16-pyridinium ceramide analogue LCL-30 to induce cell death in vitro by mitochondrial targeting. The aim of the current study was to translate these results to an in vivo model. We found that LCL-30 accumulated in mitochondria in the murine colorectal cancer cell line CT-26 and reduced cellular ATP content, leading to dose-and time-dependent cytotoxicity. Although the mitochondrial levels of sphingosine-1-phosphate (S1P) became elevated, transcription levels of ceramide-metabolising enzymes were not affected. In mice, LCL-30 was rapidly absorbed from the peritoneal cavity and cleared from the circulation within 24 h, but local peritoneal toxicity was doselimiting. In a model of subcutaneous tumour inoculation, LCL-30 significantly reduced the proliferative activity and the growth rate of established tumours. Sphingolipid profiles in tumour tissue also showed increased levels of S1P. In summary, we present the first in vivo application of a long-chain pyridinium ceramide for the treatment of experimental metastatic colorectal cancer, together with its pharmacokinetic parameters. LCL-30 was an efficacious and safe agent. Future studies should identify an improved application route and effective partners for combination treatment.

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“…20 In the liver, it has been indicated that S1P may play a role in wound healing through increased proliferation and contraction of stellate cells in vitro, 28 and that it exerts an inhibitory effect on growth factor-induced DNA synthesis in hepatocytes. 29 However, the effect of S1P on SECs has remained unclear in alcoholic liver disease, in which platelets appear to play an important role in sinusoidal microcirculation. Platelets have a highly active form of sphingosine kinase that rapidly converts sphingosine into S1P and have a relative deficiency of sphingosine lyase, which is the enzyme responsible for S1P catabolism and breakdown.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-phosphate protects rat liver sinusoidal endothelial cells from ethanol-induced apoptosis: Role of intracellular calcium and nitric oxide

et al. 2006

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In alcoholic liver disease, ethanol-induced damage to sinusoidal endothelial cells (SECs) appears to be important in the progression of liver damage. However, little is known about the mechanisms responsible for protection of SECs against ethanol-induced injury. To elucidate the role of sphingosine 1-phosphate (S1P), which is stored in platelets and may be released from them on their activation, we investigated the effect of S1P on rat liver SECs in primary culture. Pretreatment of cells with 1 mol/L S1P attenuated ethanol-induced apoptosis. Electron microscopy confirmed this protective effect of S1P on damaged SECs in liver tissues after perfusion of ethanol. In the absence of ethanol, S1P increased DNA synthesis as determined via incorporation of bromodeoxyuridine. S1P also ameliorated the decreased DNA synthesis of cells induced by ethanol. Addition of S1P to cells induced an increase in intracellular calcium concentrations and NO production in cells. Western blotting revealed that S1P significantly induced the activation of endothelial NO synthase (eNOS), but not Akt, and that S1P-induced activation of eNOS was blocked by trifluoperazine, a calmodulin inhibitor. Furthermore, N G -nitro-L-arginine methyl ester, a NO synthase inhibitor, cancelled the effect of S1P on DNA synthesis, apoptosis, and NO production in vitro as well as the protective effect of S1P on cell damage in situ. In conclusion, the biological effect of S1P is at least partially mediated by Ca 2؉ -sensitive eNOS activation and subsequent NO formation; extracellular S1P could contribute to sinusoidal protection and remodeling in alcoholic liver injury. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

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Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5

Cited by 86 publications

References 59 publications

Enhancement of Sphingosine 1-Phosphate-Induced Phospholipase C Activation During G0-G1 Transition in Rat Hepatocytes

Enhancement of Sphingosine 1-Phosphate-Induced Phospholipase C Activation During G0-G1 Transition in Rat Hepatocytes

Mitochondrially targeted ceramide LCL-30 inhibits colorectal cancer in mice

Sphingosine 1-phosphate protects rat liver sinusoidal endothelial cells from ethanol-induced apoptosis: Role of intracellular calcium and nitric oxide

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