Abstract 6232: Ulipristal acetate, a selective progesterone receptor modulator, induces cell death via inhibition of STAT3/CCL2 signaling pathway in uterine sarcoma

Abstract Purpose: Ulipristal acetate (UPA) is used for the treatment of uterine leiomyoma as a selective progesterone receptor modulator. Until now, there has been no experimental research on the effect of UPA on uterine sarcoma. In this study, we examined the efficacy of UPA in uterine sarcoma with in vitro and in vivo animal models. Experimental Design: The cytotoxicity of UPA was determined in uterine sarcoma cell lines (MES-SA, SK-UT-1, and SK-LMS-1) by MTT and caspase-3 activity assays. A migration assay was done using a Transwell chamber, and MMP-2 was measured with its specific ELISA kit. Apoptotic genes and signaling pathways affected by UPA were analyzed by complementary DNA (cDNA) microarray of uterine sarcoma cell lines and western blot, respectively. The in vivo efficacy of UPA was examined in uterine sarcoma cell line- and patient-derived xenograft mice models. Results: UPA inhibited cell growth and increased apoptosis in cell lines including uterine sarcoma (MES-SA) and leiomyosarcoma (SK-UT-1 and SK-LMS-1) in a dose-dependent manner. UPA also inhibited cell migration and the expression of MMP-2. cDNA microarray analysis revealed that CCL2 was commonly down-regulated by UPA in investigated cell lines. The UPA-mediated inhibition of CCL2 expression was confirmed by ELISA. The phosphorylation and the total expression of STAT3, downstream from the CCL2 signaling pathway, was also inhibited by UPA. We also found that UPA reduced cell growth and increased caspase-3 activity in primary culture cells from leiomyosarcoma patient-derived xenografts (PDX-C). Moreover, we found that STAT3/CCL2 inhibition by UPA was independent of the expression of progesterone receptor. In vivo studies with MES-SA and SK-UT-1 cell line-derived xenografts and a PDX model with leiomyosarcoma demonstrated that UPA significantly decreased tumor growth. Conclusions: UPA had significant anti-tumor effects in uterine sarcoma through the STAT3/CCL2 signaling pathway and might be a potential therapeutic agent to treat this disease. Citation Format: Jae Ryoung Hwang, Young-Jae Cho, Ji-Yoon Ryu, Ju-Yeon Choi, Jung-Joo Choi, Jeong-Won Lee. Ulipristal acetate, a selective progesterone receptor modulator, induces cell death via inhibition of STAT3/CCL2 signaling pathway in uterine sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6232.