Abstract
Ulipristal acetate (UPA), a selective progesterone receptor modulator, is used for the treatment of uterine fibroids and selectively inhibits the proliferation and inflammation of leiomyoma cells. As few studies have focused on the molecular biological mechanism of UPA in Ishikawa endometrial cancer cells, we aimed to identify the effects of UPA on these cells. Ishikawa cells were treated with different concentrations of UPA. Cell viability and colony formation assays were performed to assess the growth of cancer cells, whereas invasion and migration assays were used to measure cell motility and invasiveness. Western blotting, caspase 3/7 assay, TUNEL assay, and flow cytometry were performed to analyze apoptosis. Moreover, expression levels of the proinflammatory cytokines oncostatin M, its receptor, interleukin 6, and interleukin 8 were examined using quantitative real-time PCR. UPA decreased cell viability and growth, thereby inhibiting cell migration and invasion via induction of apoptosis. Contrary to expectation, stand-alone application of UPA increased the expression of the proinflammatory cytokines but concomitant use of UPA and the estrogen receptor antagonist ICI 182,720 decreased it. These data revealed a novel dual role of UPA: It could attenuate cell growth via activation of apoptosis while simultaneously provoking the activation of proinflammatory cytokines in endometrial cancer cells. These indicate that the combination of UPA and an estrogen receptor antagonist may be useful in suppressing the secretion of proinflammatory cytokines by UPA alone.
Highlights
Progesterone controls several reproductive functions, such as endometrial decidual alteration, regulation of implantation, mammary epithelial development, and regulation of GnRH pulse secretion, and is one of the female hormones secreted by the corpus luteum, which is mainly composed of granulosa and theca cells, after ovulation
Ishikawa cells were used because they recognize well-differentiated carcinoma cells and high expressions of progesterone receptor (PR) according to a previous report [22]. Quantitative realtime (qRT)-PCR revealed that Ulipristal acetate (UPA) upregulated the expression levels of PR and PR-B in a dose-dependent manner (Figure 1A, B)
Western blotting using Ishikawa cells treated with UPA at 10 and 40 μM for 48 h and those treated without UPA showed that UPA dosedependently increased the expression levels of Bax, cleaved PARP, and p53, a proapoptotic protein (Figure 3A, B, D and suppl Figure 1), but decreased the expression level of Bcl-2, an antiapoptotic protein (Figure 3C and suppl Figure 1)
Summary
Progesterone controls several reproductive functions, such as endometrial decidual alteration, regulation of implantation, mammary epithelial development, and regulation of GnRH pulse secretion, and is one of the female hormones secreted by the corpus luteum, which is mainly composed of granulosa and theca cells, after ovulation. Studies have reported that progesterone is involved in the development and growth of uterine fibroids [1]. Uterine fibroids are the most frequently occurring hormonedependent benign tumors in the smooth musculature of the uterus in females at sexual maturation [2]. Ulipristal acetate (UPA), a selective progesterone receptor modulator (SPRM), has. Been gaining attention for the treatment of uterine fibroids in recent years. SPRMs are known to mainly bind to the progesterone receptor (PR) and exert agonistic or antagonistic activity depending on the tissue
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