Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins

Vogt, Katja; Mahajan-Thakur, Shailaja; Wolf, Robert H.; Bröderdorf, Susanne; Vogel, Conny; Böhm, Andreas; Gräler, Markus H.; Oswald, Stefan; Greinacher, Andreas; Kroemer, Heyo K.; Jedlitschky, Gabriele; Rauch, Bernhard

doi:10.1160/th17-04-0291

Cited by 33 publications

(28 citation statements)

References 47 publications

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“…This difference is attributed to platelets that release S1P during coagulation. 17,18 As of today, two S1P transporters have been identified in platelets, the ATPdependent multidrug resistance protein 4 (Mrp4) 19 and the major facilitator superfamily transporter 2b (Mfsd2b). 20 Interpretations of S1P measurements in clinical settings, however, are hampered not only by the high variability of circulating S1P concentrations found in humans, with a reference interval for serum-S1P between 0.53 and 1.24 nmol/mL, 21 but also by seemingly contradictory observations made depending on whether serum-S1P or plasma-S1P was measured.…”

Section: Introductionmentioning

confidence: 99%

Determinants of Serum- and Plasma Sphingosine-1-Phosphate Concentrations in a Healthy Study Group

Daum

Winkler

Moritz

et al. 2020

TH Open

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Introduction To correctly interpret plasma- or serum-sphingosine-1-phosphate (S1P) concentrations measured in clinical studies it is critical to understand all major determinants in healthy controls. Methods Serum- and plasma-S1P from 174 healthy blood donors was measured by liquid chromatography-tandem mass spectrometry and correlated to clinical laboratory data. Selected plasma samples, 10 with high and 10 with low S1P concentrations, were fractionated into very low-density lipoprotein (VLDL)-, low density lipoprotein (LDL)-, high density lipoprotein (HDL)-, and lipoprotein-free fractions. S1P was then measured in each fraction to determine its distribution. Results The mean S1P concentration in serum (1.04 ± 0.24 nmol/mL) was found 39% higher compared with plasma (0.75 ± 0.16 nmol/mL) and overall was not different between men and women. Only when stratified for age and gender, older women were found to exhibit higher circulatory S1P levels than men. In plasma, S1P levels correlate to red blood cell (RBC) counts but not to platelet counts. Conversely, serum-S1P correlates to platelet counts but not to RBC counts. In addition, eosinophil counts are strongly associated with serum-S1P concentrations. Both serum- and plasma-S1P correlate to total cholesterol but not to HDL-C. The distribution of S1P between VLDL-, LDL-, HDL-, and lipoprotein-free fractions is independent of total plasma-S1P concentrations. S1P concentrations in HDL but not in LDL are highly variable. Conclusion These data indicate S1P concentrations in plasma and serum to be differentially associated with cell counts and S1P carrier proteins. Besides platelets, eosinophil counts are identified as a novel determinant for serum-S1P concentrations further suggesting a role for S1P in eosinophil pathologies.

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Section: Introductionmentioning

confidence: 99%

Determinants of Serum- and Plasma Sphingosine-1-Phosphate Concentrations in a Healthy Study Group

Daum

Winkler

Moritz

et al. 2020

TH Open

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“…Finally, S1P was investigated, as there are reports that both ABCC1 and ABCC4 are capable of transporting S1P [ 29 , 38 ]. Figure 8 d shows the results of the S1P ELISA.…”

Section: Resultsmentioning

confidence: 99%

“…Given that we observed the effects of ABCC4 knockdown on the migration of both MCF-7 and MDA-MB-231 cells, this might argue that it is not due simply to PGE 2 efflux; however, further investigation with MDA-MB-231 cells is needed. Finally, we investigated the efflux of S1P, as levels of S1P have previously been implicated in breast cancer [ 62 ], and both ABCC1 and ABCC4 are capable of transporting S1P [ 29 , 38 ]. Although the knockdown of ABCC1 or ABCC4 did not show a significant effect on extracellular levels of S1P, the inhibition of both ABCC1 and ABCC4 with MK571 did decrease the amount of S1P effluxed.…”

Section: Discussionmentioning

confidence: 99%

Roles of ABCC1 and ABCC4 in Proliferation and Migration of Breast Cancer Cell Lines

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Shabir

Brown

et al. 2020

IJMS

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ABCC1 and ABCC4 utilize energy from ATP hydrolysis to transport many different molecules, including drugs, out of the cell and, as such, have been implicated in causing drug resistance. However recently, because of their ability to transport signaling molecules and inflammatory mediators, it has been proposed that ABCC1 and ABCC4 may play a role in the hallmarks of cancer development and progression, independent of their drug efflux capabilities. Breast cancer is the most common cancer affecting women. In this study, the aim was to investigate whether ABCC1 or ABCC4 play a role in the proliferation or migration of breast cancer cell lines MCF-7 (luminal-type, receptor-positive) and MDA-MB-231 (basal-type, triple-negative). The effects of small molecule inhibitors or siRNA-mediated knockdown of ABCC1 or ABCCC4 were measured. Colony formation assays were used to assess the clonogenic capacity, MTT assays to measure the proliferation, and scratch assays and Transwell assays to monitor the cellular migration. The results showed a role for ABCC1 in cellular proliferation, whilst ABCC4 appeared to be more important for cellular migration. ELISA studies implicated cAMP and/or sphingosine-1-phosphate efflux in the mechanism by which these transporters mediate their effects. However, this needs to be investigated further, as it is key to understand the mechanisms before they can be considered as targets for treatment.

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“…Serum S1P levels have been determined in the low micromolar range and appear to persist at least in healthy human subjects independently of age and gender [ 34 ]. During conditions of elevated platelet activation such as an acute coronary syndrome, S1P can be released from human platelets in large quantities—a process which depends on thromboxane formation and the ATP-binding cassette transporter ABCC4 (MRP4) [ 37 , 38 , 39 ]. Altering S1P levels in serum or in specific tissues appears as a novel therapeutic strategy to modulate cellular functions under certain pathophysiological conditions, i.e., we could recently show that stimulating osteoblast activity via inhibition of S1P degradation by targeting the S1P lyase is a new concept to treat osteoporosis [ 40 ].…”

Section: Tgf-β Pars and Sphingosine-1-phosphate As A Mediator Bementioning

confidence: 99%

Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer

Ungefroren

Gieseler

Kaufmann

et al. 2018

IJMS

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Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed in these pathologies or display mutual regulation of their signaling components, which is mediated in part through sphingosine kinases and sphingosine-1-phosphate and indicative of an intimate signaling crosstalk between the two pathways. In the first part of this review, we summarize the various regulatory interactions that have been discovered so far according to the organ/tissue in which they were described. In the second part, we highlight the types of signaling crosstalk between TGF-β on the one hand and PAR2/PAR1 on the other hand. Both ligand–receptor systems interact at various levels and by several mechanisms including mutual regulation of ligand–ligand, ligand–receptor, and receptor–receptor at the transcriptional, post-transcriptional, and receptor transactivation levels. These mutual interactions between PAR2/PAR1 and TGF-β signaling components eventually result in feed-forward loops/vicious cycles of matrix deposition and malignant traits that exacerbate fibrosis and oncogenesis, respectively. Given the crucial role of PAR2 and PAR1 in controlling TGF-β receptor activation, signaling, TGF-β synthesis and bioactivation, combining PAR inhibitors with TGF-β blocking agents may turn out to be more efficient than targeting TGF-β alone in alleviating unwanted TGF-β-dependent responses but retaining the beneficial ones.

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Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins

Cited by 33 publications

References 47 publications

Determinants of Serum- and Plasma Sphingosine-1-Phosphate Concentrations in a Healthy Study Group

Determinants of Serum- and Plasma Sphingosine-1-Phosphate Concentrations in a Healthy Study Group

Roles of ABCC1 and ABCC4 in Proliferation and Migration of Breast Cancer Cell Lines

Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer

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