Bufalin suppresses endometriosis progression by inducing pyroptosis and apoptosis

J Endocrinol. 2018 Jun;237(3):255-269. doi: 10.1530/JOE-17-0700. Epub 2018 Apr 10.

Abstract

The steroid receptor coactivator (SRC)-1 isoform/estrogen receptor (ER)-β axis has an essential role in endometriosis progression. In this context, therefore, bufalin was employed as a 'tool compound' to evaluate inhibitors of SRC in alternative endometriosis treatment. Bufalin effectively suppressed the growth of primary human endometrial stroma cells isolated from endometriosis patients compared to women without endometriosis and immortalized human endometrial epithelial and stromal cells expressing the SRC-1 isoform compared to their parental cells in vitroIn vivo, compared to the vehicle, bufalin treatment significantly suppressed the growth of endometriotic lesions in mice with surgically induced endometriosis because bufalin disrupted the functional axis of SRC-1 isoform/ERβ by increasing SRC-1 isoform protein stability, hyperactivating the transcriptional activity of the SRC-1 isoform and degrading the ERβ protein by proteasome 26S subunit, non-ATPase 2 in endometriotic lesions. Bufalin treatment elevated the apoptosis signaling in epithelial cells of endometriotic lesions. In stromal cells of endometriotic lesions, bufalin treatment increased the levels of pyroptosis markers (caspase 1 and the active form of interleukin 1β) and reduced proliferation. In addition, bufalin treatment increased the expression levels of endoplasmic reticulum-stress (ERS) markers (PKR-like ER kinase, protein disulfide isomerase and binding immunoglobulin) in endometriotic lesions. Collectively, the bufalin-induced disruption of the SRC-1 isoform/ERβ axis might induce apoptosis, pyroptosis and ERS signaling in endometriotic lesions, causing the suppression of endometriosis. Therefore, future generations of SRC-modulators could be employed as an alternative medical approach for endometriosis treatment.

Keywords: apoptosis; bufalin; endometriosis; estrogen receptor β; pyroptosis; steroid receptor coactivator 1 isoform.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Bufanolides / pharmacology*
  • Cells, Cultured
  • Disease Progression
  • Down-Regulation / drug effects
  • Endometriosis / pathology*
  • Endometrium / drug effects
  • Endometrium / pathology
  • Endometrium / physiology
  • Female
  • Fertility / drug effects
  • HeLa Cells
  • Humans
  • Litter Size / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Pyroptosis / drug effects*
  • Signal Transduction / drug effects
  • Stromal Cells / drug effects
  • Stromal Cells / pathology
  • Stromal Cells / physiology
  • Uterine Diseases / pathology*

Substances

  • Bufanolides
  • bufalin