sphingosine-1-phosphate and Endometriosis

Endometriosis is a common condition in women of reproductive age, but its current interventions are unsatisfactory. Recent research discovered a dysregulation of the sphingosine 1-phosphate (S1P) signaling pathway in endometriosis and showed a positive outcome by targeting it. The S1P axis participates in a series of fundamental pathophysiological processes. This narrative review is trying to expound the reported and putative (due to limited reports in this area for now) interactions between the S1P axis and endometriosis in those pathophysiological processes, to provide some perspectives for future research. In short, S1P signaling pathway is highly activated in the endometriotic lesion. The S1P concentration has a surge in the endometriotic cyst fluid and the peritoneal fluid, with the downstream dysregulation of its receptors. The S1P axis plays an essential role in the migration and activation of the immune cells, fibrosis, angiogenesis, pain-related hyperalgesia, and innervation. S1P receptor (S1PR) modulators showed an impressive therapeutic effect by targeting the different S1P receptors in the endometriosis model, and many other conditions resemble endometriosis. And several of them already got approval for clinical application in many diseases, which means a drug repurposing direction and a rapid clinical translation for endometriosis treatments.

Topics: Endometriosis; Female; Humans; Lysophospholipids; Receptors, Lysosphingolipid; Sphingosine

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid, noteworthy for its involvement both in the modulation of various biological processes and in the development of many diseases. S1P signaling can be either pro or anti-inflammatory, and the sphingosine kinase (SphK)-S1P-S1P receptor (S1PR) axis is a factor in accelerating the growth of several cells, including endometriotic cells and fibrosis. Gynecologic disorders, including endometriosis, adenomyosis, and uterine fibroids are characterized by inflammation and fibrosis. S1P signaling and metabolism have been shown to be dysregulated in those disorders and they are likely implicated in their pathogenesis and pathophysiology. Enzymes responsible for inactivating S1P are the most affected by the dysregulation of S1P balanced levels, thus causing accumulation of sphingolipids within these cells and tissues. The present review highlights the past and latest evidence on the role played by the S1P pathways in common gynecologic disorders (GDs). Furthermore, it discusses potential future approaches in the regulation of this signaling pathway that could represent an innovative and promising therapeutical target, also for ovarian cancer treatment.

Topics: Endometriosis; Female; Fibrosis; Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptors

Topics: Endometriosis; Female; Humans; Male; Reactive Oxygen Species; Sphingolipids; Sphingosine

To study the molecular mechanisms involved in the appearance of the fibrotic trait in endometriosis by investigating whether the signaling pathway of the bioactive sphingolipid sphingosine 1-phosphate (S1P) was altered in endometriotic lesions.. Case-control laboratory study.. University research institute and university hospital.. A total of 75 women, with and without endometriosis, were included in the study.. Endometrial samples were obtained from women affected (n = 15 endometrioma [OMA]; n = 30 deep infiltrating endometriosis [DIE]) and not (n = 30) by endometriosis by means of laparoscopic surgery, followed by clinical and imaging investigation and checking for the expression of fibrosis markers and genes implicated in S1P metabolism and signaling by means of real-time polymerase chain reaction.. The role of the S1P signaling axis in endometriosis-associated fibrosis was studied in vitro, where RNA interference approaches were used to investigate if S1P synthesis by sphingosine kinases (SKs) and specific S1P receptors (S1PRs) are implicated in the profibrotic effect of the cytokine transforming growth factor (TGF) β1.. The S1P signaling axis may represent a useful biomarker or innovative pharmacologic target for endometriosis.

Topics: Case-Control Studies; Cells, Cultured; Dose-Response Relationship, Drug; Endometriosis; Female; Fibrosis; HeLa Cells; Humans; Lysophospholipids; Sphingosine; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; Transforming Growth Factor beta1

Topics: Endometriosis; Female; Humans; Lysophospholipids; Phosphates; Sphingosine

There is growing evidence that sphingosine 1-phosphate (S1P) is involved in inflammatory diseases. As endometriosis is known as an inflammatory disease, we investigated the role of S1P system in the development of endometriosis.. The expression of sphingosine kinase (SphK) 1 in endometriosis lesions was examined by immunohistochemistry. The cystic fluid of ovarian cysts/tumors were obtained to measure S1P concentrations. Endometriotic stromal cells (ESC) derived from endometrioma were used for in vitro experiments.. Sphingosine kinase 1 was detected in epithelium and stromal cells of endometriotic lesions. The mean S1P concentration in the cystic fluid of endometriomas was higher than that in nonendometriomas significantly (98.2 nM vs less than 1.5 nM,. The present study for the first time proved that the SphK-S1P-S1PR axis play a role of accelerating inflammation and growth of endometriotic cells.

Topics: Adult; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Endometriosis; Endometrium; Female; Gene Expression; Humans; Interleukin-6; Lysophospholipids; Sphingosine

To investigate key genes expression of the sphingosine-1-phosphate pathway in endometriotic tissues.. A case-control laboratory study.. Tertiary care university hospital.. A total of 31 women, with (n = 16) and without (n = 15) endometriosis took part in the study.. After surgical excision with pathological analysis, endometrial specimens were obtained from women affected or not by endometriosis.. SPHK1-2, SGPP1-2, SGPL1, SPHKAP, and S1PR1-5 messenger RNA expression by quantitative real-time polymerase chain reaction (PCR) in the endometrium of 15 disease-free women, 16 eutopic and 16 ectopic endometrium of endometriosis-affected women. The S1PR1 and S1PR2 expression were further investigated by immunohistochemistry.. The SGPP2 expression was decreased in eutopic and ectopic endometrium of endometriosis-affected women (1.7- and 16.7-fold, respectively). The SGPP1, weakly expressed in healthy endometrium, is up-regulated in endometriosis-affected women (11.9- and 64.7-fold, respectively), but its expression remains low. The SGPL1 expression was decreased in ectopic endometrium (3.3-fold) and SPHKAP expression was increased in ectopic endometrium (112.6-fold) compared with endometrium of disease-free women. In endometriosis-affected women, S1PR3 expression was decreased in eutopic and ectopic endometrium (2.1- and 6.3-fold, respectively); S1PR2 and S1PR1 expression was increased in eutopic (2.5-fold) and ectopic endometrium (2.6-fold). These increases were confirmed at the protein levels by immunohistochemistry.. Expression of the enzymes implicated in the regulation of the sphingosine-1-phosphate level balance and of its receptors is overall heavily deregulated in endometriotic lesions in favor of a decreased sphingosine-1-phosphate catabolism. Our results plead for a role of the sphingosine pathway in establishing and survival of endometriotic lesions.

Topics: Aldehyde-Lyases; Analysis of Variance; Case-Control Studies; Endometriosis; Endometrium; Female; Hospitals, University; Humans; Immunohistochemistry; Lysophospholipids; Membrane Proteins; Ovarian Diseases; Paris; Phosphoric Monoester Hydrolases; Phosphotransferases (Alcohol Group Acceptor); Real-Time Polymerase Chain Reaction; Receptors, Lysosphingolipid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sphingosine; Sphingosine-1-Phosphate Receptors