Paeonol alleviates migration and invasion of endometrial stromal cells by reducing HIF-1α-regulated autophagy in endometriosis

Abstract

Background: Dysregulated migration and invasion of endometrial stromal cells is implicated in the pathogenesis of endometriosis. Hypoxia functions as critical microenvironmental factor that results in promotion of endometrial stromal cells migration and invasion through upregulation of autophagy. Paeonol functioned as a tumor suppressor in human ovarian cancer and promoted cytoprotective autophagy. However, the role of paeonol in hypoxia-induced autophagy in endometriosis remains unknown. Methods: Stromal cells were isolated from endometriotic patients by enzymatic digestion of ectopic endometrial tissues, and then characterized by immunohistochemical analysis of cytoskeleton 19 (CK19) and vimentin. Cellular morphology was evaluated under microscope. Cell viability, proliferation and apoptosis of stromal cells were assessed by Cell Counting Kit-8, EdU labeling and flow cytometry, respectively. Wound healing and transwell assays were performed to detect metastasis of the stromal cells. Hypoxia-induced autophagy was evaluated through immunohistochemistry and western blot. Results: Paeonol treatment dosage dependently decreased cell proliferation and metastasis of the ectopic endometrial stromal cells (ecESCs), while promoted the cell apoptosis. Hypoxia-induced autophagy in the ecESCs was repressed by paeonol through down-regulation of LC3-II/LC3-I and Beclin-1, while up-regulation of p62. Hypoxia-inducible factor-1α (HIF-1α) was reduced post paeonol treatment, and paeonol-induced increase of p62 and decrease of LC3-II/LC3-I and Beclin-1 were reversed by over-expression of HIF-1α. Over-expression of HIF-1α also attenuated the suppressive effect of paeonol on cell growth of ecESCs. Conclusions: Paeonol attenuated HIF-1α-induced promotion of ecESCs migration and invasion through reducing autophagy, and reduced HIF-1α-induced endometriotic lesion in rats, providing potential therapeutic strategy for the treatment of endometriosis.

Moutan Cortex extract inhibited the proliferation and migration of endometrial stromal cells by inhibiting OPN-induced, MAPK-mediated MMP9 activation

“…Quercetin could inhibit proliferation in VK2/E6E7 and End1/E6E7 cells to act as a natural therapeutic to reduce and treat endometriosis (Park et al, 2019). Additionally, active ingredients paeonol and β-sitosterol also had analogous function in treating endometriosis (Ilhan et al, 2019;Pang et al, 2021).…”

Hypoxia and the endometrium: An indispensable role for HIF-1α as therapeutic strategies

“…Certain Chinese herbal medicine ingredients have shown promise in significantly reducing the area of endometriotic lesions, largely by inhibiting HIF-1α, which has been validated in both mouse models and in vitro studies using endometriotic tissues. However, the detailed mechanism of interaction related to these molecules remains to be studied [ [152] , [153] , [154] , [155] , [156] ]. Notably, downregulating the HIF-1α pathway in certain cells can effectively protect the physiological changes of the normal endometrium, such as the immune effect of dNK during decidualization, which depends on the stabilization of HIF-1α proteins [ 46 ].…”

A comprehensive overview of exosome lncRNAs: emerging biomarkers and potential therapeutics in endometriosis

“…In the ectopic endometrium and serum of endometriosis patients, aHIF is abundantly expressed. Hence, exosome lncRNA-aHIFs are being investigated as potential molecular markers for the detection of endometriosis ( 115 , 116 ). a-HIF plays a role in increasing angiogenesis in endometriosis and is strongly expressed in the endometriotic stromal cells (ECSCs) of patients with endometriosis.…”