Progesterone receptor antagonist provides palliative effects for uterine leiomyoma through a Bcl-2/Beclin1-dependent mechanism.

Lindong Zhang,Pingping Liu,Shihong Cui,Quanling Feng,Zhiting Wang

doi:10.1042/bsr20190094

Abstract

Uterine leiomyoma is the most common benign smooth muscle tumor of uterus in women of reproductive age, with a high lifetime incidence. Nowadays, the exploration on the pharmacotherapies, such as progesterone receptor antagonist (PRA) requires more attention. Hence, the current study aimed to examine whether mifepristone, a PRA, influences the autophagy and apoptosis of uterine leiomyoma cells. Primary uterine leiomyoma cells were collected from 36 patients diagnosed with uterine leiomyoma to establish PR-M-positive (PR-M[+]) cells. The lentiviral vector overexpressing or silencing PR-M was subsequently delivered into one part of PR-M(+) cells in order to evaluate the role of PR-M in PR-M(+) cells. The results obtained revealed that cell viability was increased, while cell autophagy and apoptosis were diminished in the PR-M(+) cells treated with overexpressed PR-M, whereby the Bcl-2 level was elevated and the level of Beclin1 was reduced. An opposite trends were identified following treatment with knockdown of PR-M. Mifepristone at different concentrations (low, moderate, or high) was then applied to treat another part of the PR-M(+) cells. Mifepristone was identified to promote cell autophagy and apoptosis, decrease Bcl-2 level and increase Beclin1 level, accompanied by weakened interaction between Bcl-2 and Beclin1. Moreover, these effects of mifepristone on PR-M(+) cells were enhanced with increasing of the concentration. Taken together, the present study present evidence indicates the ability of PRA to regulate the Bcl-2/Beclin1 axis, ultimately promoting the autophagy and apoptosis of uterine leiomyoma cells, highlighting that PRA serves as a promising therapeutic target for the treatment of uterine leiomyoma.

Highlights

Uterine leiomyoma, commonly referred to as uterine fibroids, remains the most common type of benign tumor afflicting the smooth muscle of the uterus, with the lifetime prevalence exceeding approximately 70% in the general population [1]
The normal endometrial stromal cells served as the control, with our investigations revealing that the progesterone receptor antagonist (PRA)/B antibody was effective [22]
With the results in the above section detailing the inhibitory role of progesterone and its receptors (PRs)-M in the PR-M(+) cell autophagy and apoptosis, we examined the hypothesis that PRA may have a reverse effect

Summary

Introduction

Commonly referred to as uterine fibroids, remains the most common type of benign tumor afflicting the smooth muscle of the uterus, with the lifetime prevalence exceeding approximately 70% in the general population [1]. Uterine leiomyoma is characterized by heavy or prolonged menstrual bleeding and resultant anemia generally affecting women of reproductive age, which may significant affect the quality of life and fertility [2]. Surgeries (e.g. hysterectomy and myomectomy by hysteroscopy or laparoscopy) and pharmacotherapies (e.g. oral contraceptives, progestins, and GnRH analogs) represent the first-line therapeutic approaches for patients diagnosed with uterine leiomyoma [3,4]. Emerging evidence has demonstrated that progesterone and its receptors (PRs) may act to promote the uterine leiomyomata cell viability [5]. In order to find an alternative measure to treat uterine leiomyoma and reduce the need for invasive surgery, treatments with anti-progestins and selective PR modulators (SPRMs), like progesterone receptor antagonist (PRA), require further investigation

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