Sphingosine 1-phosphate receptor, a new therapeutic direction in different diseases

Chen, Hongyu; Wang, Junmin; Zhang, Caiyun; Ding, Peilun; Tian, Shuxia; Chen, Junming; Ji, Guang; Wu, Tao

doi:10.1016/j.biopha.2022.113341

Cited by 36 publications

(13 citation statements)

References 114 publications

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“…Activation of ERK1/2 is well known to be involved in the regulation of numerous molecular events within a cell and has been shown to be activated through several S1P receptors ( 53 ). Therefore, we evaluated whether S1P-mediated ERK1/2 activation could be responsible for the transcriptional changes induced by S1P in our human myometrial cell models.…”

Section: Resultsmentioning

confidence: 99%

Sphingosine 1-Phosphate Activates S1PR3 to Induce a Proinflammatory Phenotype in Human Myometrial Cells

et al. 2023

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One of the common mechanisms responsible for obstetric complications, affecting millions of women every year, is abnormal uterine contractility. Despite the critical importance of this process for women’s health, mechanisms of uterine contraction regulation remain poorly understood. The initiation of uterine smooth muscle (myometrial) contraction is an inflammatory process, accompanied by upregulation of pro-inflammatory genes and cytokine release. In this study, we show that sphingolipid metabolism is activated during human labor and that sphingosine 1-phosphate (S1P), the main bioactive sphingolipid, may modify the myometrial pro-inflammatory phenotype. Our data in both primary and immortalized human myometrial cells show that exogenous S1P induces a pro-inflammatory gene signature and upregulates the expression of known inflammatory markers of parturition, such as IL8 and COX2. Using expression of IL8 as a readout for S1P activity in myometrial cells, we established that these S1P effects are mediated through the activation of S1P receptor 3 (S1PR3) and downstream activation of ERK1/2 pathways. Inhibition of S1PR3 in human myometrial cells attenuates upregulation of IL8, COX2 and JUNB both at the mRNA and protein levels. Furthermore, activation of S1PR3 with a receptor-specific agonist recapitulated the effects seen after treatment with exogenous S1P. Collectively, these results suggest a signaling pathway activated by S1P in human myometrium during parturition and propose new targets for development of novel therapeutics to alter uterine contractility during management of preterm labor or labor dystocia.

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Section: Resultsmentioning

confidence: 99%

Sphingosine 1-Phosphate Activates S1PR3 to Induce a Proinflammatory Phenotype in Human Myometrial Cells

et al. 2023

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“…S1P, a bioactive lipid secondary messenger 43 , regulates complex cellular functions in the TME, acting as a signalling molecule in cell-cell communication 44 . S1P exerts its physiological functions predominantly by binding to S1PRs (S1PR1-S1PR5) 34,45 , members of the G-protein-coupled receptor superfamily. In this study, the therapeutic effect of OX40 activation was associated with an increase in intracellular S1P levels, which was not abolished on S1PR knockdown.…”

Section: Discussionmentioning

confidence: 99%

OX40 expressed in endothelial cells facilitates tumor cells to escape from T-cell surveillance through S1P-YAP axis

Zhang,

He,

Zhao

et al. 2024

Preprint

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Activation of immune cells is currently one of the most promising approaches for the cancer treatment. However, clinical trials for T-cell activation therapy have not reached expected results without explicit reasons. In the present study, we report that the co-stimulatory molecule OX40 is highly expressed in endothelial cells (ECs) of tumor tissues. Clinically, high expression of OX40 in ECs is negatively associated with the prognosis of tumor patients, and this is irrelevant to T-cell activation or not. Analysis of conditional OX40 loss- and gain-of-function transgenic mice demonstrated that OX40 signals promote angiogenesis and facilitate the tumour development. Mechanistically, Lgr5+ cancer stem cells induced high OX40 expression in tumour ECs via EGF-STAT3 signal transduction. In ECs, activated OX40 interacted with Spns2, obstructing sphingosine-1-phosphate (S1P) export and resulting in its intracellular accumulation. S1P directly bound to YAP, disrupting its interaction with the LATS1 kinase and promoting YAP nuclear translocation. Finally, the YAP inhibitor Verteporfin enhanced the anti-tumour effects of the OX40 agonist. In addition, their combination exhibited greater efficacy than that of the OX40 agonist and anti-PD-1 antibody. Together, the findings revealed a unexpected pro-tumour functions of OX40 activation in ECs, highlighting the impact of non-immune cell compartment on immunotherapy and the complexity of tumour microenvironment.

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“…Since the importance of S1P in cancer varies depending on the cancer type, subtype, degree of progression, presence or absence of metastases and the organs to which it spreads, and the cancer microenvironment, clinical application of therapies targeting S1P signaling will require identifying the patient population for whom the therapy will be most effective [ 230 , 231 ]. Therefore, the development of therapies targeting S1P signaling requires the selection of target patient groups, the development of S1P signaling inhibitors, and consideration of combination therapy with anti-cancer drugs and molecular-targeted drugs.…”

Section: Targeting S1p As Therapy For Advanced Breast Cancermentioning

confidence: 99%

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

Nagahashi,

Miyoshi

2024

IJMS

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In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.

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Sphingosine 1-phosphate receptor, a new therapeutic direction in different diseases

Cited by 36 publications

References 114 publications

Sphingosine 1-Phosphate Activates S1PR3 to Induce a Proinflammatory Phenotype in Human Myometrial Cells

Sphingosine 1-Phosphate Activates S1PR3 to Induce a Proinflammatory Phenotype in Human Myometrial Cells

OX40 expressed in endothelial cells facilitates tumor cells to escape from T-cell surveillance through S1P-YAP axis

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

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