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.
Highlights
The lipid mediator sphingosine 1-phosphate (S1P) regulates a variety of cellular processes including inflammation, oncogenesis, metastasis, survival, stem cell behavior and the formation of microvascular networks, which provides nourishment to cancerous cells [1]
Abbreviations used in the table are defined as follows: AKT, AKT8 virus oncogene cellular homolog; G6PT, glucose 6-phosphatase; MT1-MMP, membrane-type-1 matrix metalloproteinase; NS, not studied; PAI-1, plasminogen activator inhibitor-1; SK1-I, sphingosine kinase 1-inhibitor; SPP2, S1P phosphatase 2; uPAR, urokinase-type plasminogen activator receptor; ↑, increased; ↓, reduced
Evidence from diverse in vitro and in vivo studies indicate that S1P, its metabolizing enzymes, and S1P receptors (S1PRs) play significant roles in glioblastoma multiforme (GBM) cell fate determination
Summary
The lipid mediator sphingosine 1-phosphate (S1P) regulates a variety of cellular processes including inflammation, oncogenesis, metastasis, survival, stem cell behavior and the formation of microvascular networks, which provides nourishment to cancerous cells [1]. Despite several studies showing the biological functions of S1P, it seems to be challenging to define the specific mechanism(s) involved in a particular cancer type. This most likely is owed to the complex nature of the S1P signaling system as S1P varies in cellular origin, cell type-specific actions, abundance or deficiency of the specific S1P receptors, and intracellular environment [3]. Several studies have associated alteration in S1P levels, and the involvement of its receptors and metabolite enzymes in many types of cancer pathophysiology. High expressions of S1PR1, S1PR3, and the S1P generating enzyme SphK1 have been reported in breast cancer patients [7]. We exclusively focus on the literature that provides insights into the role of S1P signaling in the pathogenesis of GBM
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