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

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. Setting: Academic laboratory. Exposure: Leiomyoma and myometrial cells were treated with S1P, as well as with selective antagonists for S1P specific G-protein coupled receptors (S1PR) and secondarily with inhibitors of extracellular-signal regulated kinase 1/2 (ERK1/2) and ezrin. Main outcome measure(s): Cellular proliferation and fibrogenesis. Bromodeoxyuridine (BrdU) cell proliferation assay was employed to measure DNA synthesis and proliferation, while Western Blot analysis was used to assess the expression of the fibrotic markers N-cadherin, alpha Smooth Muscle Actin (αSMA), transgelin and Collagen type I alpha 1. Result(s): S1P stimulates cellular proliferation of leiomyoma but not myometrial cells. The mitogenic effect elicited by S1P relies on the specific engagement of its specific receptor S1P2 and is mediated by ERK1/2 and ezrin activation. Furthermore, S1P exerts a pro-fibrotic effect in a S1PR-dependent manner in leiomyoma but not myometrial cells. Conclusion(s): These results, beside 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.