Les récepteurs de la sphingosine 1-phosphate

Cuvillier, Olivier

doi:10.1051/medsci/20122811013

Cited by 17 publications

(7 citation statements)

References 37 publications

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“…We also show that Akt represents a mechanistic link between SphK1/S1P signaling and mTOR signaling, as SphK1 silencing abrogates the Akt/mTOR stimulation. Because Akt signaling can be activated by all Gi-coupled S1P receptor subtypes 5 , 65 and because S1P has been shown to be released from hypoxic cells, 24 , 59 , 66 we explored the effects of the neutralization of extracellular S1P with anti-S1P monoclonal antibody sphingomab. 13 Similar to our recent data showing that sphingomab could block HIF-1α accumulation and activity in prostate cancer cell and animal models, 24 our findings firmly establish the contribution of extracellular S1P in the regulation of HIF-2α as the silencing of S1P exporter Spns2 as well as the use of sphingomab markedly reduced HIF-2α in all ccRCC subtypes.…”

Section: Discussionmentioning

confidence: 99%

Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer

et al. 2016

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The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway has been reported to modulate the expression of the canonical transcription factor hypoxia-inducible HIF-1α in multiple cell lineages. HIF-2α is also frequently overexpressed in solid tumors but its role has been mostly studied in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, where HIF-2α has been established as a driver of a more aggressive disease. In this study, the role of SphK1/S1P signaling with regard to HIF-2α was investigated in various cancer cell models including ccRCC cells. Under hypoxic conditions or in ccRCC lacking a functional von Hippel-Lindau (VHL) gene and expressing high levels of HIF-2α, SphK1 activity controls HIF-2α expression and transcriptional activity through a phospholipase D (PLD)-driven mechanism. SphK1 silencing promotes a VHL-independent HIF-2α loss of expression and activity and reduces cell proliferation in ccRCC. Importantly, downregulation of SphK1 is associated with impaired Akt and mTOR signaling in ccRCC. Taking advantage of a monoclonal antibody neutralizing extracellular S1P, we show that inhibition of S1P extracellular signaling blocks HIF-2α accumulation in ccRCC cell lines, an effect mimicked when the S1P transporter Spns2 or the S1P receptor 1 (S1P1) is silenced. Here, we report the first evidence that the SphK1/S1P signaling pathway regulates the transcription factor hypoxia-inducible HIF-2α in diverse cancer cell lineages notably ccRCC, where HIF-2α has been established as a driver of a more aggressive disease. These findings demonstrate that SphK1/S1P signaling may act as a canonical regulator of HIF-2α expression in ccRCC, giving support to its inhibition as a therapeutic strategy that could contribute to reduce HIF-2 activity in ccRCC.

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Section: Discussionmentioning

confidence: 99%

Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer

et al. 2016

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“…Bioactive sphingolipids, including sphingosine kinases (SKs) and their product S1P, have been demonstrated to be involved in the regulation of cancer growth, metastasis and drug resistance ( 19 ). It has been well established that S1P exerts its intracellular and extracellular pro-survival and drug resistance functions through S1PR1 ( 20 , 21 ); therefore, SK/S1P/S1PR1 signaling appears to be a promising therapeutic target for cancer. In the present study, it was shown that S1PR1 was significantly upregulated in hepatocellular carcinoma tissues, consistent with a previous study ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

microRNA-148a inhibits hepatocellular carcinoma cell invasion by targeting sphingosine-1-phosphate receptor 1

Zhang

Liu

2014

Experimental and Therapeutic Medicine

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microRNA (miR)-148a has been shown to act as an important suppressor in numerous human malignancies and is markedly downregulated in hepatocellular carcinoma; however, the role of miR-148a in the regulation of hepatocellular carcinoma cell invasion, as well as the underlying mechanism, has never been studied. In the present study, the expression level of miR-148a was found to be significantly decreased in hepatocellular carcinoma tissues and HepG2 cells when compared with that in the normal adjacent tissues. Furthermore, a novel target of miR-148a was found, sphingosine-1-phosphate receptor 1 (S1PR1), whose expression was negatively regulated by miR-148a at a post-transcriptional level in hepatocellular carcinoma HepG2 cells. Upregulation of miR-148a by transfection with miR-148a mimics notably suppressed HepG2 cell invasion, similar to the effect of the SIPR1 downregulation induced by SIPR1-specific small interfering RNA, while the restoration of S1PR1 expression reversed the inhibitory effect of miR-148a upregulation on HepG2 cell invasion. Accordingly, the current study suggests that miR-148a plays an inhibitory role in the regulation of hepatocellular carcinoma cell invasion by directly targeting S1PR1.

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“…S1P is generated by sphingosine kinases (SphKs), of which there are two isoenzymes (SphK1 and SphK2), and is degraded by the S1P lyase (SPL) to hexadecenal and ethanolamine phosphate [ 44 ]. Once produced, S1P can work as an intracellular signaling molecule or be secreted to act as an autocrine or paracrine molecule by binding to five specific high-affinity G protein-coupled receptors (GPCR), named S1P 1–5 [ 13 , 45 , 46 ]. Subcellular localization of SphK1 and SphK2 isoenzymes and subsequent compartimentalization of generated S1P appear to be crucial in dictating the biological effect of S1P [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain

Dominguez

Maddelein

Pucelle

et al. 2018

acta neuropathol commun

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BackgroundAlzheimer’s disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides and hyperphosphorylated tau protein accompanied by neuronal loss. Aβ accumulation has been associated with an impaired sphingosine 1-phosphate (S1P) metabolism. S1P is generated by sphingosine kinases (SphKs), of which there are two isoenzymes SphK1 and SphK2, and degraded by the sphingosine 1-phosphate lyase (SPL). We previously reported, that both a decrease in SphK1 expression and an increase in SPL expression, correlated with amyloid deposits in the entorhinal cortex of AD brains, suggesting a global loss of pro-survival S1P in AD neurons. SphK2 contribution has also been examined in AD yielding to conflicting results that may reflect the complexity of SphK2 regulation. The subcellular localization of SphK2, hence the compartmentalization of generated S1P, is recognized to play a crucial role in dictating either its pro-survival or pro-apoptotic functions. We therefore aimed at studying the expression of SphK2 and notably its subcellular localization in brain tissues from patients with AD.ResultsWe report that a decrease in SphK2 protein cytosolic expression correlated with the density of amyloid deposits in a cohort of 25 post-mortem brains. Interestingly, we observed that the equilibrium between cytoplasmic and nuclear SphK2 is disrupted and showed that SphK2 is preferentially localized in the nucleus in AD brain extracts as compared to control extracts, with a marked increase of cleaved SphK2.ConclusionsOur results suggest that a shift in the subcellular localization of the S1P generating SphK2 may compromise the well established pro-survival cytosolic S1P by favoring the production of nuclear S1P associated with adverse effects in AD pathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0527-z) contains supplementary material, which is available to authorized users.

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Les récepteurs de la sphingosine 1-phosphate

Cited by 17 publications

References 37 publications

Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer

Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer

microRNA-148a inhibits hepatocellular carcinoma cell invasion by targeting sphingosine-1-phosphate receptor 1

Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain

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