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Review
. 2017 Nov 17;18(11):2448.
doi: 10.3390/ijms18112448.

Sphingosine 1-phosphate (S1P) Signaling in Glioblastoma multiforme-A Systematic Review

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Free PMC article
Review

Sphingosine 1-phosphate (S1P) Signaling in Glioblastoma multiforme-A Systematic Review

Shailaja Mahajan-Thakur et al. Int J Mol Sci. .
Free PMC article

Abstract

The multifunctional sphingosine-1-phosphate (S1P) is a lipid signaling molecule and central regulator in the development of several cancer types. In recent years, intriguing information has become available regarding the role of S1P in the progression of Glioblastoma multiforme (GBM), the most aggressive and common brain tumor in adults. S1P modulates numerous cellular processes in GBM, such as oncogenesis, proliferation and survival, invasion, migration, metastasis and stem cell behavior. These processes are regulated via a family of five G-protein-coupled S1P receptors (S1PR1-5) and may involve mainly unknown intracellular targets. Distinct expression patterns and multiple intracellular signaling pathways of each S1PR subtype enable S1P to exert its pleiotropic cellular actions. Several studies have demonstrated alterations in S1P levels, the involvement of S1PRs and S1P metabolizing enzymes in GBM pathophysiology. While the tumorigenic actions of S1P involve the activation of several kinases and transcription factors, the specific G-protein (Gi, Gq, and G12/13)-coupled signaling pathways and downstream mediated effects in GBM remain to be elucidated in detail. This review summarizes the recent findings concerning the role of S1P and its receptors in GBM. We further highlight the current insights into the signaling pathways considered fundamental for regulating the cellular processes in GMB and ultimately patient prognosis.

Keywords: S1P receptor signaling; glioblastoma multiforme; sphingosin-1-phosphate.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Biosynthesis of ceramide and sphingosine-1-phosphate (S1P) production. Ceramide de novo synthesis typically originates from the condensation of serine, palmitoyl-CoA and fatty acids—a multistep enzyme-catalyzed process. Ceramide can be transformed reversibly (indicated by the two-way arrows) into sphingomyelin by sphingomyelinase or to glycosphingolipids. It is further metabolized to sphingosine by ceramidase. Sphingosine can then be phosphorylated into S1P by the sphingosine kinase isoforms 1 and 2 (SphK1/2). This phosphorylation can be reverted by the S1P phosphatases 1 and 2 (SPP1/2), or irreversible degradation by S1P lyase can occur. S1P produced intracellularly is exported out of the cell via ATP-binding cassette transporters (ABC) transporters or spinster homolog 2 (Spns2), dependent on the cell type. Subsequently, it can act either in an autocrine or paracrine manner by binding to one of its receptors (S1PR1–5) to regulate multifaceted cellular functions via G-protein-mediated signaling. S1P promotes key processes of glioblastoma multiforme (GBM) pathogenesis which involve cell proliferation, invasion, migration, survival, tumor growth, oncogenesis and development of microvascular networks. Additional abbreviations used in the figure are defined as follows: SMase, sphingomyelinase; SMS, sphingomyelin synthase; S1PRs, S1P receptor(s).
Figure 2
Figure 2
Schematic diagram depicting guanine nucleotide-binding protein (Gi)-mediated S1PRs activation and multiple signaling pathways in glioblastoma. S1PRs via stimulation of the Gi may simultaneously activate MAPK-ERK1/2, c-jun N-terminal kinases (JNK), phospholipase C (PLC), phosphoinositide 3-kinase (PI3K) and p38 pathways in glioma cells. Following the activation of downstream signaling, ERK1/2 facilitates the co-expression and activation of c-jun, c-fos and the early growth response (Egr-1)/fibroblast growth factor (FGF-2) system respectively. Cell cycle arrest by CCND2 (cyclin D2) gene expression and the PLC/Ca2+ system is responsible for proliferation. Sphingosine kinase 1 (SphK1) signaling is necessary for the maintenance of urokinase plasminogen activator (uPA) expression and the basal invasive activity of glioma cells by a receptor-independent mechanism. While phosphorylation of SphK1 by ERK1/2 regulates S1P production and spiral signaling PI3k/ATK pathways through the activated downstream targets, mechanistic target of rapamycin (mTOR) and metalloproteases (MMPs) lead to angiogenesis and survival. On the other hand, p38 signaling induces migration. Additional abbreviations used in the figure are defined as follows: DAG, diacylglycerol; ERK1/2, extracellular signal-regulated kinase 1 and 2; Gi, guanine nucleotide-binding protein; IP3, inositol-1, 4, 5-triphosphate; MEK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLC, phospholipase C; ↑, increased.
Figure 3
Figure 3
Graphic of S1PR pathways involved in RhoA (Ras homolog gene family, member A) and transcription factor activation in glioma cells. A Rho-like subfamily has been identified which becomes activates via the stimulation of G12/13-protein subunit of S1PRs. The guanine nucleotide exchange factor activates downstream signaling intermediates such as Rho GTPases (guanosine triphosphate hydrolase enzymes) namely CDC42 (cell division control protein 42 homolog), RhoA, and Rac1 (Ras-related C3 botulinum toxin substrate 1). An Rho-kinase-dependent increase in the phosphorylation of the myosin light chain (MLC) by inhibiting the myosin-binding subunit (MBS) causes myofibril reorganization, contraction, and activation of downstream transcriptional effectors. The RhoA-mediated (Ras homolog gene family) transcriptional network involves activator protein 1 (AP1), yes-associated protein (YAP), myocardin-related transcription factor A (MRTF-A), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Resulting target genes are involved in the regulation of invasion, proliferation, and differentiation of glioma cells. Inversely, nuclear phosphatase and tensin homolog (PTEN) expression can reduce AKT phosphorylation and consequently inhibit proliferation. On the other hand, Rac1 inhibits migration. Additional abbreviations used in the figure are defined as follows: GEF, guanine nucleotide exchange factor; PKD, protein kinase D; ROCK, RhoA kinase; SRF, serum response factor; ↓inhibition.
Figure 4
Figure 4
Illustrative scheme of Gq-protein (Gq)-mediated S1P effects in glioblastoma. Activation of S1PR2 and S1PR3 through stimulation of Gq-subunit boosts calcium mobilization and PLC/PKC/ERK1/2 signaling. Following either pathway increases invasion and proliferation by activation of transcription factor activating protein 1 (AP1) and NF-kB-mediated CCND2 expression, respectively. Conversely, S1P also induces cyclo-oxygenase 2 (COX-2) expression and therefore prostaglandin E2 (PGE2) production, in turn, transactivates prostaglandin receptors (EP1-4) receptors leading to a Gi-dependent intracellular signaling mechanism (e.g. activation of the BCL-2/BCL-XL family members). Subsequently, this cascade upturns oxidative stress which is responsible for the transformation of a normal cell to tumor cell, its metastasis and thus survival. Additional abbreviations used in the figure are defined as follows: BCL2; B-cell lymphoma 2; BCL-XL, B-cell lymphoma-extra-large; Gi, Gi-protein; ↑, increased.

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