Sphingosine Kinases Signalling in Carcinogenesis

Marfè, Gabriella; Mirone, Giovanna; Shukla, Arvind Kumar; Stefano, Carla Di

doi:10.2174/1389557515666150227105415

Cited by 23 publications

(22 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We further showed that TRPC1‐mediated Ca 2+ entry was required to induce basal SPHK1 activity and S1P generation because expression of a pore‐deleted TRPC1 mutant increased SPHK1 promoter activity, SPHK1 expression, and S1P levels. We also showed that SK1‐I, a specific inhibitor of SPHK1 (41, 56‐58), was comparatively less effective in disrupting basal barrier function in TRPC1‐null ECs, especially at 20 μM, supporting the central concept that loss of TRPC1 augments basal SPHK1 expression and thereby increases AJs integrity. The question arose that preexisting S1P should be able to ligate S1PR1 and protect against barrier dysfunction even though no new S1P was being made as a result of inhibition of SPHK1 by SK1‐I.…”

Section: Discussionsupporting

confidence: 60%

Transient receptor potential channel 1 maintains adherens junction plasticity by suppressing sphingosine kinase 1 expression to induce endothelial hyperpermeability

et al. 2015

View full text Add to dashboard Cite

Stability of endothelial cell (EC) adherens junctions (AJs) is central for prevention of tissue edema, the hallmark of chronic inflammatory diseases including acute respiratory distress syndrome. Here, we demonstrate a previously unsuspected role of sphingosine kinase 1 (SPHK1) in the mechanism by which transient receptor potential channel 1 (Trpc1)-mediated Ca(2+) entry destabilizes AJs. Trpc1(-/-) monolayers showed a 2.2-fold increase in vascular endothelial (VE)-cadherin cell-surface expression above wild-type (WT) monolayers. Thrombin increased endothelial permeability (evident by a 5-fold increase in interendothelial gap area and 60% decrease in transendothelial electrical resistance) in WT but not Trpc1(-/-) ECs. Trpc1(-/-) mice resisted the hyperpermeability effects of the edemagenic agonists used and exhibited 60% less endotoxin-induced mortality. Because sphingosine-1-phosphate (S1P) strengthens AJs, we determined if TRPC1 functioned by inhibiting SPHK1 activity, which generates S1P. Intriguingly, Trpc1(-/-) ECs or ECs transducing a TRPC1-inactive mutant showed a 1.5-fold increase in basal SPHK1 expression compared with WT ECs, resulting in a 2-fold higher S1P level. SPHK1 inhibitor SK1-I decreased basal transendothelial electrical resistance more in WT ECs (48 and 72% reduction at 20 and 50 μM, respectively) than in Trpc1(-/-) ECs. However, SK1-I pretreatment rescued thrombin-induced EC permeability in Trpc1(-/-) ECs. Thus, TRPC1 suppression of basal SPHK1 activity enables EC-barrier destabilization by edemagenic agonists.

show abstract

Section: Discussionsupporting

confidence: 60%

Transient receptor potential channel 1 maintains adherens junction plasticity by suppressing sphingosine kinase 1 expression to induce endothelial hyperpermeability

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The SphKs family includes two distinct isoforms of SphK1 and SphK2, of which SphK1 is the predominant form in the lung, kidney, blood, and spleen [13]. Studies have shown that SphK1/S1P axis plays a crucial role in tumorigenesis, hormonal therapy and chemotherapy resistance [14].…”

Section: Introductionmentioning

confidence: 99%

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

Wang

Zhu

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The underlying molecular mechanisms involved in sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and the present study aims to address this issue. Methods: Small interfering RNA (siRNA) and microRNA inhibitor transfection was performed to block the expression of SphK1, bone morphogenetic protein receptor II (BMPRII) and microRNA-21 (miR-21). Gene expression levels of SphK1, BMPRII and inhibitor of DNA binding 1 (Id1) were detected by immunoblotting, miR-21 expression level was examined with qRT-PCR, and S1P production was measured by ELISA. Additionally, PASMC proliferation was determined by BrdU incorporation assay. Results: Our results indicated that PDGF increased the expression of SphK1 protein and S1P production, up-regulated miR-21 expression, reduced BMPRII and Id1 expression, and promoted PASMCs proliferation. Pre-silencing of SphK1 with siRNA reversed PDGF-induced S1P production, miR-21 up-regulation, BMPRII and Id1 down-regulation, as well as PASMC proliferation. Pre-inhibition of miR-21 also blocked BMPRII and Id1 down-regulation as well as PASMC proliferation caused by PDGF. Knockdown of BMPRII down-regulated Id1 expression in PASMCs. We further found that inhibition of PI3K/Akt and ERK signaling pathways, particularly ERK cascade, suppressed PDGF-induced above changes. Conclusion: Our study indicates that SphK1/S1P pathway plays an important role in PDGF-induced PASMC proliferation via miR-21/BMPRII/Id1 axis and targeting against SphK1/S1P axis might be a novel strategy in the prevention and treatment of pulmonary arterial hypertension (PAH).

show abstract

“…Mammals encode two SK isozymes (SK1 and SK2) that have different subcellular localizations, functions and pharmacology (3, 6, 7). For example, overexpression of SK1 is oncogenic (8, 9), while transfection with SK2 was originally reported to inhibit cell growth and to induce apoptosis (10).…”

Section: Introductionmentioning

confidence: 99%

A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors

Britten

Garrett‐Mayer

Chin

et al. 2017

Clinical Cancer Research

135

116

View full text Add to dashboard Cite

Purpose Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and pro-inflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of ABC294640, a first-in-class orally-available inhibitor of SK2. Experimental Design Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results 22 patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting and fatigue. Among the four patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and two were unable to complete Cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the Recommended Phase II Dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions At 500 mg bid, ABC294640 is well tolerated and achieves biologically-relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.

show abstract

Sphingosine Kinases Signalling in Carcinogenesis

Cited by 23 publications

References 0 publications

Transient receptor potential channel 1 maintains adherens junction plasticity by suppressing sphingosine kinase 1 expression to induce endothelial hyperpermeability

Transient receptor potential channel 1 maintains adherens junction plasticity by suppressing sphingosine kinase 1 expression to induce endothelial hyperpermeability

SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway

A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors

Contact Info

Product

Resources

About