Abstract
Endometriosis (EMS) is an estrogen-dependent gynecological disease with a low autophagy level of ectopic endometrial stromal cells (eESCs). Impaired NK cell cytotoxic activity is involved in the clearance obstruction of the ectopic endometrial tissue in the abdominopelvic cavity. Protopanaxadiol (PPD) and protopanaxatriol (PPT) are two metabolites of ginsenosides, which have profound biological functions, such as anti-cancer activities. However, the role and mechanism of ginsenosides and metabolites in endometriosis are completely unknown. Here, we found that the compounds PPD, PPT, ginsenoside-Rg3 (G-Rg3), ginsenoside-Rh2 (G-Rh2), and esculentoside A (EsA) led to significant decreases in the viability of eESCs, particularly PPD (IC50 = 30.64 µM). In vitro and in vivo experiments showed that PPD promoted the expression of progesterone receptor (PR) and downregulated the expression of estrogen receptor α (ERα) in eESCs. Treatment with PPD obviously induced the autophagy of eESCs and reversed the inhibitory effect of estrogen on eESC autophagy. In addition, eESCs pretreated with PPD enhanced the cytotoxic activity of NK cells in response to eESCs. PPD decreased the numbers and suppressed the growth of ectopic lesions in a mouse EMS model. These results suggest that PPD plays a role in anti-EMS activation, possibly by restricting estrogen-mediated autophagy regulation and enhancing the cytotoxicity of NK cells. This result provides a scientific basis for potential therapeutic strategies to treat EMS by PPD or further structural modification.
Highlights
Endometriosis (EMS) is a common estrogen-dependent gynecological disease that is defined by the attachment ofThere is strong evidence to support the important role of estrogen dependence, progesterone resistance, and defects in the immune system in EMS, leading to the enhanced benign tumor-like behaviors of refluxed endometrium[6,7,8,9].Official journal of the Cell Death Differentiation AssociationZhang et al Cell Death and Disease (2018)9:574Current medical therapies (e.g., progestins, androgens, gonadotropin-releasing hormone (GnRH) agonists, and aromatase inhibitors) focus primarily on reducing the systemic levels of estrogens, but these are of limited effectiveness, with frequent recurrence and considerable side effects[1]
We evaluated the effects of PPD, PPT, G-Rg3, G-Rh2, and esculentoside A (EsA) on endometrial stromal cells (eESCs) and normal ESCs in vitro
Further analysis showed that the expression levels of anti-apoptosis molecules B-cell lymphoma (Bcl)xL and Bcl-2, and proliferation-related molecules Ki-67 and proliferating cell nuclear antigen (PCNA) in PPDtreated eESCs were obviously decreased compared with those of control eESC and EsA-treated eESCs (Fig. 1d, e)
Summary
Endometriosis (EMS) is a common estrogen-dependent gynecological disease that is defined by the attachment ofThere is strong evidence to support the important role of estrogen dependence, progesterone resistance, and defects in the immune system (e.g., impaired cytotoxic activity of NK cells) in EMS, leading to the enhanced benign tumor-like behaviors of refluxed endometrium (such as unrestrained proliferation and aggressive invasion)[6,7,8,9].Official journal of the Cell Death Differentiation AssociationZhang et al Cell Death and Disease (2018)9:574Current medical therapies (e.g., progestins, androgens, gonadotropin-releasing hormone (GnRH) agonists, and aromatase inhibitors) focus primarily on reducing the systemic levels of estrogens, but these are of limited effectiveness, with frequent recurrence and considerable side effects[1]. Accumulating evidence has indicated that the level of autophagy in both the ectopic and eutopic endometrium of patients with EMS is decreased[7,11,12,13,14,15]. This aberrantly low autophagy is associated with the highly proliferative and lowly apoptotic capacities of ectopic endometrial stromal cells (eESCs)[7,11,12,13,14]. A new therapeutic strategy should be urgently required, that is, targeting autophagy and immunomodulation simultaneously
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