Sphingosine 1-phosphate acts as proliferative and fibrotic cue in leiomyoma cells.

Abstract

Objective: To determine whether the bioactive sphingolipid sphingosine 1-phosphate (S1P) modulates cellular proliferation and synthesis of fibrotic proteins in leiomyoma differently than myometrial cells.

Design: A basic science study using human leiomyoma and myometrial cells.

Patient(s): Not applicable. This is an in vitro study performed on cellular models.

Setting: Academic laboratory.

Intervention(s): Leiomyoma and myometrial cells were treated with S1P, as well as with selective antagonists for S1P-specific G protein-coupled receptors and secondarily with inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2) and ezrin.

Main outcome measure(s): The main outcome measures included cellular proliferation and fibrogenesis. Bromodeoxyuridine Cell Proliferation Assay was employed to measure deoxyribonucleic acid synthesis and proliferation, whereas western blot analysis was used to assess the expression of the fibrotic markers N-cadherin, α-smooth muscle actin, transgelin, and collagen type I alpha 1.

Result(s): Sphingosine 1-phosphate stimulates cellular proliferation of leiomyoma but not myometrial cells. The mitogenic effect elicited by S1P relies on the engagement of its specific receptor S1P₂ and is mediated by ERK1/2 and ezrin activation. Furthermore, S1P exerts a profibrotic effect in a S1P-specific G protein-coupled receptor-dependent manner in leiomyoma but not myometrial cells.

Conclusion(s): These results, besides extending the knowledge on the molecular mechanism underlying uterine leiomyoma development and fibrosis, demonstrate the pathogenetic role of S1P in leiomyoma and support the rationale for targeting S1P signaling pathway as innovative potential treatment.