S1PR4 Promotes Cell Viability, Invasion, and Glycolysis via the Mammalian Target of Rapamycin Signaling Pathway in Endometriosis.

Abstract

OBJECTIVE: Endometriosis is a chronic gynecological disorder that can cause infertility in women of reproductive age, and its clinical treatment still faces significant challenges. However, the pathogenesis of endometriosis remains unclear. METHODS: S1PR4 knockdown and overexpression were constructed in primary ectopic endometrial stromal cells (EESCs) with or without the glycolysis inhibitor 2-deoxy-D-glucose and normal endometrial stromal cells (ESCs) with or without the mTOR signaling pathway inhibitor AZD8055, respectively. CCK-8 and Transwell assays were used to evaluate the viability and invasive capabilities. The cellular glycolytic capacity was assessed by measuring the extracellular acidification rate and lactate levels in the cell culture supernatant. An endometriosis mouse model was established in vivo, and histopathological changes in the endometrium were analyzed by hematoxylin-eosin staining. The expression of S1PR4, LDHA, and p-mTOR in endometrium and ESCs was assessed using qRT-PCR, Western blotting, or immunofluorescence. RESULTS: Glycolytic levels were increased in EESCs, and inhibiting glycolysis in vitro reduced the viability and invasive capabilities of EESCs, as well as suppressed the growth of ectopic lesions in vivo. S1PR4 was abnormally overexpressed in endometriosis, and knocking down S1PR4 inhibited the viability, invasion, and glycolysis of EESCs, along with downregulation of p-mTOR expression. Conversely, overexpression of S1PR4 promoted the viability, invasion, and glycolysis of ESCs via the mTOR signaling pathway. CONCLUSIONS: In endometriosis, S1PR4 enhances cellular glycolysis by activating the mTOR signaling pathway, thereby promoting the viability and invasion of EESCs.