SCM-198 Prevents Endometriosis by Reversing Low Autophagy of Endometrial Stromal Cell via Balancing ERα and PR Signals

Front Endocrinol (Lausanne). 2022 Jun 15;13:858176. doi: 10.3389/fendo.2022.858176. eCollection 2022.

Abstract

Background: Endometriosis (EMS), an endocrine-related inflammatory disease, is characterized by estrogen and progesterone imbalance in ectopic lesions. However, its pathogenic mechanism has not been fully elucidated. While SCM-198 is the synthetic form of leonurine and has multiple pharmacological activities such as antioxidation and anti-inflammation, it remains unknown whether it could inhibit the progress of EMS by regulating estrogen signaling and inflammation.

Methods: The therapeutic effects of SCM-198 on EMS and its potential mechanism were analyzed by establishing EMS mouse models and performing an RNA sequencing (RNA-seq) assay. ELISA was performed to detect estrogen and tumor necrosis factor (TNF) -α concentrations in normal endometrial stromal cells (nESCs) and ectopic endometrial stromal cells (eESCs) with or without SCM-198 treatment. Western blotting, RNA silencing, and plasmid overexpression were used to analyze the relationship between inflammation, endocrine factors, and autophagy and the regulatory activity of SCM-198 on the inflammation-endocrine-autophagy axis.

Results: Increased estrogen-estrogen receptor (ER) α signaling and decreased progesterone receptor isoform B (PRB) expression synergistically led to a hypo-autophagy state in eESCs, which further inhibited the apoptosis of eESCs. The high expression of TNF-α in eESCs enhanced the antiapoptotic effect mediated by low autophagy through the activation of the aromatase-estrogen-ERα signaling pathway. SCM-198 inhibited the growth of ectopic lesions in EMS mice and promoted the apoptosis of eESCs both in vivo and in vitro. The apoptotic effect of SCM-198 on eESCs was attained by upregulating the autophagy level via the inhibition of the TNF-α-activated aromatase-estrogen-ERα signal and the increase in PRB expression.

Conclusion: Inflammation facilitated the progress of EMS by disrupting the estrogen regulatory axis. SCM-198 inhibited EMS progression by regulating the inflammation-endocrine-autophagy axis.

Keywords: EMS; SCM-198; TNF-α; autophagy; estrogen; progesterone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aromatase / genetics
  • Aromatase / metabolism
  • Autophagy
  • Endometriosis* / metabolism
  • Endometriosis* / prevention & control
  • Endometrium / pathology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism
  • Estrogens / pharmacology
  • Female
  • Gallic Acid / analogs & derivatives
  • Humans
  • Mice
  • Receptors, Progesterone / metabolism
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Estrogen Receptor alpha
  • Estrogens
  • Receptors, Progesterone
  • Tumor Necrosis Factor-alpha
  • leonurine
  • Gallic Acid
  • Aromatase