Pathogenic Role of the Sphingosine 1-Phosphate (S1P) Pathway in Common Gynecologic Disorders (GDs): A Possible Novel Therapeutic Target

Abstract

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.

Shared Pathogenic and Therapeutic Characteristics of Endometriosis, Adenomyosis, and Endometrial Cancer: A Comprehensive Literature Review

“…For instance, Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that originates from sphingomyelin catabolism. It plays a role in the growth of various cells, including those involved in endometriosis or adenomyosis [ 32 ].…”

“…Due to the heterogeneity of symptoms, there’s often a delay in diagnosis, and available therapeutic options are not curative. Currently, there’s increased emphasis on understanding the pathogenesis of these diseases [ 1 , 32 , 60 , 66 ].…”

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

“…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.…”

How do sphingosine-1-phosphate affect immune cells to resolve inflammation?

“…S1P promotes fibrosis in cells such as macrophages, fibroblasts, and skeletal muscle precursors, mainly by binding to pro-inflammatory cytokines such as TNF-α. In turn, it stimulates the synthesis of interleukin-1β and TGF-β in cells ( 151 ). The disruption of S1P pathway is the basis of systemic chronic metabolic inflammatory diseases, including diabetes and gastrointestinal cancer, which provides sufficient evidence for using S1P pathway modulators in treating pathological inflammation ( 152 ).…”