Mechanisms of sphingosine 1-phosphate receptor signalling in cancer

Patmanathan, Sathya Narayanan; Wang, Wei; Yap, Lee Fah; Herr, Deron R.; Paterson, Ian C.

doi:10.1016/j.cellsig.2017.03.002

Cited by 72 publications

(63 citation statements)

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“…8). S1P 3 has been shown to promote migration and invasion in many cancer types (21). Here we propose a novel mechanism where S1P 3 can promote cell invasion by up-regulating SNAI2 transcription via MRTF-A.…”

Section: Discussionmentioning

confidence: 83%

“…Some intracellular targets of S1P have been previously reported by Spiegel et al (13); however, the vast majority of the effects of S1P are mediated by 5 cognate GPCRs, the S1P receptors (S1PRs), known as S1P 1 , -2 , -3 , - 4 and - 5 (14). Depending on the receptor expression profile and the availability of the downstream effectors, the SPHK-S1P-S1PR signaling axis has been implicated in various aspects of cancer progression, including transformation, growth, survival, migration, metastasis, neovascularization and angiogenesis, and drug resistance (15)(16)(17)(18)(19)(20)(21)(22). A number of therapeutics have been developed to target components of this pathway for cancer treatment (23,24).…”

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confidence: 99%

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Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

et al. 2019

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Epithelial‐mesenchymal transition (EMT) is a critical process implicated in the initial stage of cancer metastasis, which is the major cause of tumor recurrence and mortality. Although key transcription factors that regulate EMT, such as snail family transcriptional repressor 2 (SNAI2), are well characterized, the upstream signaling pathways controlling these transcriptional mediators are largely unknown, which limits therapeutic strategies. Sphingosine 1–phosphate (S1P) is a bioactive lipid mediator, generated by sphingosine kinases (SPHK1 and SPHK2), that mainly exerts its effects by binding to the following 5 GPCRs: S1P1 to S1P5. S1P signaling has been reported to regulate different aspects of cancer progression including cell proliferation, apoptosis, and migration; nevertheless, its role in cancer metastasis, specifically via EMT, is not established. Here we show that SPHK1 expression correlates significantly with EMT score in breast cancer cell lines, and with SNAI2 in patient‐derived breast tumors. Cell‐based assays demonstrate that S1P can rapidly up‐regulate the expression of SNAI2 in breast cancer cells via the activation of cognate receptors S1P2 and S1P3. Knockdown studies suggest that S1P2 and S1P3 mediate this effect by activating myocardin‐related transcription factor A (MRTF‐A) and yes‐associated protein (YAP), respectively. Michigan Cancer Foundation 7 cells stably overexpressing S1P2 or S1P3 exhibit a more invasive phenotype, when compared to control cells. Taken together, our findings suggest that S1P produced by SPHK1 induces SNAI2 expression via S1P2‐YAP and S1P3‐MRTF‐A pathways, leading to enhanced cell invasion. Cumulatively, this study reveals a novel mechanism by which S1P activates parallel pathways that regulate the expression of SNAI2, a master regulator of EMT, and provides new insights into druggable therapeutic targets that may limit cancer metastasis. Wang, W., Hind, T., Lam, B. W. S., Herr, D. R. Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells. FASEB J. 33, 7180–7191 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 83%

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confidence: 99%

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

et al. 2019

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“…The S1P content in cells is low and is kept under control through a delicately regulated balance between its synthesis by Sphingosine kinases 1 & 2 (SphKs) and its dephosphorylation by S1P phosphatases or degradation by S1P lyase. Once produced S1P can be secreted via specific ATP-binding cassette transporters including Spns2 and exerts its extracellular functions through a family of five G-protein-coupled receptors, named S1P [1][2][3][4][5] . Thus, this inside-out signaling is critical for a variety of S1P cellular responses.…”

Section: Sphingosine 1-phosphate Signaling Controls Mitosis Olivier Cmentioning

confidence: 99%

“…Deregulation of S1P metabolism has been related to various diseases including cancer with increased S1P tissue levels. Various studies suggest the involvement of SphKs/S1P signaling in tumor progression and metastasis [1,2].Cell division or mitosis is a particularly complex and highly regulated process that allows the formation of two genetically identical daughter cells. A quality control mechanism called spindle assembly checkpoint (SAC, sometimes referred as mitotic checkpoint), ensures fidelity of chromosome segregation.…”

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Besides their structural role, sphingolipids including Sphingosine-1phosphate (S1P) have drawn attention as bioactive sphingolipid signaling molecules involved in the regulation of several processes, including cell growth, differentiation, survival, migration or immune response. It is now well established that S1P is involved in the onset or the progression of pathological conditions such as cancer, autoimmunity, cardiovascular conditions or diabetes to name a few. The S1P content in cells is low and is kept under control through a delicately regulated balance between its synthesis by Sphingosine kinases 1 & 2 (SphKs) and its dephosphorylation by S1P phosphatases or degradation by S1P lyase. Once produced S1P can be secreted via specific ATP-binding cassette transporters including Spns2 and exerts its extracellular functions through a family of five G-protein-coupled receptors, named S1P 1-5 . Thus, this inside-out signaling is critical for a variety of S1P cellular responses. Deregulation of S1P metabolism has been related to various diseases including cancer with increased S1P tissue levels. Various studies suggest the involvement of SphKs/S1P signaling in tumor progression and metastasis [1,2].Cell division or mitosis is a particularly complex and highly regulated process that allows the formation of two genetically identical daughter cells. A quality control mechanism called spindle assembly checkpoint (SAC, sometimes referred as mitotic checkpoint), ensures fidelity of chromosome segregation. The SAC prevents anaphase onset until all kinetochores are stably attached to microtubules. In the presence of unattached kinetochore, the SAC is on and the metaphase-to-anaphase transition is inhibited. Dysfunction of SAC leads to chromosome mis-segregation and aneuploidy and is implicated in tumorigenesis [3,4].We recently identified and explored a novel function of SphKs/S1P signaling during mitosis [5]. Our study began with the observation that SphK1 silencing increased the mitotic rate whereas its ectopic expression decreased it. Detailed analysis revealed a SAC-dependent mitotic delay before metaphase in cells lacking S1P. Pharmacological inhibition of SphK1 led to mitotic delay similar to SphK1 silencing indicating that mitotic function of SphK1 is related to its enzymatic activity. The prediction was that SphK1 controls mitosis through its product S1P. Indeed, cells treated with S1P, completed mitosis much faster. S1P induced SAC relaxation leading to chromosome segregation defects. However, understanding the pathophysiological consequences of S1P-induced chromosome segregation defects will require further studies. S1P may act intra-or extracellularly. To test this hypothesis we used Sphingomab TM , a highaffinity monoclonal anti-S1P antibody that neutralizes extracellular S1P [6]. First, Sphingomab completely blocked mitotic acceleration induced by both S1P and SphK1 overexpression. Second, silencing Spns2, the major S1P transporter, blocked S1P release and resulted in mitotic delay. Third, conditioned media f...

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Sphingosine 1‐Phosphate Signalling

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Donati

et al. 2019

Encyclopedia of Life Sciences

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Studies of the last two decades have clearly established that sphingosine 1‐phosphate (S1P), considered for many years a mere by‐product of the membrane phospholipid sphingomyelin catabolism, serves indeed as powerful signalling molecule. Intensive research in the field have clarified the complexity of S1P metabolism as well as the multifaceted mechanism of action of this potent lysophospholipid, which acts both as intracellular mediator, capable of regulating the properties of different proteins, and high‐affinity ligand of five specific G‐protein coupled receptors, termed S1P 1 ‐S1P 5 . In parallel, it has been progressively disclosed the versatile biological activity endowed by S1P, which appears to be crucially implicated in the control of many key parameters, ranging from cell proliferation to cell motility and survival. Besides to act as ubiquitous cellular mediator, notably, circulating S1P plays a significant physiological role. S1P concentrations are high in blood and lymph but low in tissues. S1P chemotactic gradients are indeed essential for lymphocyte egress and physiological cell trafficking. Key Concepts S1P is generated via phosphorylation of the amino alcohol sphingosine catalysed by sphingosine kinase (SphK), which exists in two isoforms: SphK1 and SphK2. Ceramide, either synthesised de novo or formed by sphingomyelin catabolism, is the precursor of sphingosine, released by ceramidase‐dependent deacylation. Intracellular production of S1P in under the control of a wide array of hormones, neurotransmitters, cytokines and growth factors. S1P is a powerful bioactive sphingolipid, which acts both as intracellular mediator and ligand of specific G‐protein coupled receptors, named S1P receptors (S1PR). There are five specific S1PR that couple to different G proteins and regulate many downstream signalling pathways. The biological functions of S1P depend on the relative expression of these receptors. In many instances, S1P acts via inside‐out signalling, intracellularly generated in response to extracellular cues, is exported outside the cell and binds S1PR in paracrine or autocrine fashion. S1P 1 is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation. S1P concentrations are elevated in plasma and lymph compared to the interstitial fluid of tissues. This S1P gradient is essential for many of the physiologic functions provided by extracellular S1P.

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Mechanisms of sphingosine 1-phosphate receptor signalling in cancer

Cited by 72 publications

References 127 publications

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

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Sphingosine 1‐Phosphate Signalling

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