Parthenolide repressed endometriosis induced surgically in rats: Role of PTEN/PI3Kinase/AKT/GSK-3β/β-catenin signaling in inhibition of epithelial mesenchymal transition

PI3K/AKT/GSK-3β/β-catenin signaling pathway is a triggering factor for epithelial to mesenchymal transition (EMT) which plays a pivotal role in the pathogenesis of endometriosis. Parthenolide is a sesquiterpene lactone extract that has anti-inflammatory, analgesic and anticancer properties. Hence, we investigated the effect of parthenolide against EMT in the endometrial tissue implants and immortalized epithelial endometriotic cell lines 12Z. Twenty- four female Rats with surgically induced endometriosis were treated with parthenolide (2, 4 mg/kg), for 4 weeks. Endometriotic cell line 12Z was used to identify the effect of parthenolide on the wound healing, cellular migration and invasion properties of endometriotic cells. Parthenolide decreased the endometriotic implant tissue expression of total PI3K, PI3K-p85, p-AKT, p/total AKT, p-GSK-3β, P/total GSK-3β, and nβ-catenin, as well as increased E-cadherin and decreased vimentin mRNA expression. Parthenolide upregulated PTEN immunoreactivity as well as the endometriotic tissue caspase-3, caspase-9, BAX levels while reducing Bcl2 level. Additionally, parthenolide decreased endometriotic tissue implants surface area and histopathological score of the epithelial growth. Our findings showed that parthenolide in a dose dependent manner inhibited PI3K/AKT/GSK-3β/nβ-catenin cascade via enhancement of PTEN with subsequent inhibition of EMT evidenced by elevation of the epithelial marker, E-cadherin and reduction of mesenchymal marker, vimentin, of the endometriotic implants in addition to reversal of invasion and migration properties of epithelial endometriotic cell lines. These findings provide a valuable therapeutic approach for treatment of endometriosis. •Epithelial to mesenchymal transition is a key factor for endometriosis development.•The PI3K/Akt/GSK-3β/ β-catenin signaling is a central player in cell proliferation, migration and invasion.•Parthenolide through upregulating PTEN can inhibit the PI3K/Akt/GSK-3β/β-catenin mediated EMT.