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S1PR4 Promotes Cell Viability, Invasion, and Glycolysis via the Mammalian Target of Rapamycin Signaling Pathway in
Huizhi Yuan1, Zhongju Xie2, Minqing Feng1
1Department of Gynaecology, Foshan Women and Children Hospital Affiliated to Guangdong Medical University, Foshan, China.
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.
Insights
Sphingosine-1-phosphate receptor 4 (S1PR4) promotes endometriosis by enhancing cellular glycolysis via the mTOR pathway. Inhibiting S1PR4 or glycolysis reduces cell viability and invasion, offering potential therapeutic targets for endometriosis.
Area of Science:
- Gynecology
- Cell Biology
- Molecular Biology
Background:
- Endometriosis is a chronic gynecological disorder impacting women of reproductive age, often leading to infertility.
- The precise pathogenesis of endometriosis remains incompletely understood, hindering effective clinical treatment.
- Cellular metabolism, particularly glycolysis, is increasingly recognized as a potential factor in gynecological disorders.
Purpose of the Study:
- To investigate the role of Sphingosine-1-phosphate receptor 4 (S1PR4) in the pathogenesis of endometriosis.
- To elucidate the relationship between S1PR4, cellular glycolysis, and the mTOR signaling pathway in endometriosis.
- To evaluate the therapeutic potential of targeting S1PR4 or glycolysis in endometriosis.
Main Methods:
- Primary ectopic endometrial stromal cells (EESCs) and normal endometrial stromal cells (ESCs) were manipulated for S1PR4 knockdown or overexpression.
- Glycolysis was inhibited using 2-deoxy-D-glucose, and the mTOR pathway was inhibited using AZD8055.
- Cell viability, invasion, and glycolytic capacity were assessed in vitro; an endometriosis mouse model was used for in vivo validation.
Main Results:
- Ectopic endometrial stromal cells exhibited increased glycolytic levels; inhibition of glycolysis reduced EESC viability, invasion, and ectopic lesion growth in vivo.
- S1PR4 was overexpressed in endometriosis; S1PR4 knockdown decreased EESC viability, invasion, and glycolysis, while downregulating p-mTOR.
- S1PR4 overexpression promoted ESC viability, invasion, and glycolysis, mediated through the mTOR signaling pathway.
Conclusions:
- S1PR4 plays a critical role in endometriosis by enhancing cellular glycolysis through activation of the mTOR signaling pathway.
- This S1PR4-mediated enhancement of glycolysis promotes the viability and invasive capabilities of EESCs.
- Targeting S1PR4 or glycolysis presents a promising therapeutic strategy for managing endometriosis.
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