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 up-regulation 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.
Highlights
Paeonol (4-methoxy-2-hydroxyacetophenone), an active compound extracted from traditional chinese medicine, demonstrated antioxidant, anti-tumor, antiinflammatory and immunomodulatory effects [11]
The ectopic endometrial stromal cells (ecESCs) under hypoxia treatment were applied to paeonol condition
Results showed that paeonol condition dosage dependently reduced cell viability of ecESCs (Fig. 1B), while dosage dependently promoted cell apoptosis of ecESCs (Fig. 1C)
Summary
Paeonol (4-methoxy-2-hydroxyacetophenone), an active compound extracted from traditional chinese medicine, demonstrated antioxidant, anti-tumor, antiinflammatory and immunomodulatory effects [11]. Paeonol decreased vascular endothelial growth factor to enhance radiotherapy-induced apoptosis of ovarian cancer [14]. Whether paeonol has an effect on endometriosis has not been studied yet. Paeonol activated autophagy flux in ovarian cancer [15], and promoted autophagy to demonstrate anti-atherosclerotic in vascular smooth muscle cell [16]. Oxidized low-density lipoprotein-induced vascular endothelial cell autophagy was suppressed by paeonol [17]. The detailed role of paeonol on autophagy in endometriosis needs further research. This study aimed to investigate roles of paeonol on migration and invasion of isolated ectopic endometrial stromal cells (ecESCs), as well as endometriotic lesion in rats. Whether autophagy was implicated in paeonol-mediated progression of endometriosis was determined
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