Molecular mechanisms underlying mifepristone's agonistic action on ovarian cancer progression Donata Ponikwicka-Tyszko a , Marcin Chrusciel b , Joanna Stelmaszewska c , Piotr Bernaczyk d , Paulina Chrusciel e , Maria Sztachelska a , Mika Scheinin f , Mariusz Bidzinski g , Jacek Szamatowicz h , Ilpo T. Huhtaniemi b,i , Slawomir Wolczynski a,c , Nafis A. Rahman b,c, ⁎ a Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland b Institute of Biomedicine, University of Turku, Finland c Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Poland d Department of Medical Pathomorphology, Medical University of Bialystok, Poland e Central Animal Laboratory, University of Turku, Turku, Finland f Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland g Department of Gynecological Oncology, Maria Sklodowska - Curie Institute Oncology Center, Warsaw, Poland h Department of Gynecology and Gynecological Oncology, Medical University of Bialystok, Poland i Institute of Reproductive and Developmental Biology (IRDB), Imperial College London, London, UK abstract article info Article history: Received 22 January 2019 Received in revised form 14 August 2019 Accepted 16 August 2019 Available online 26 August 2019 Background: Recent clinical trials on ovarian cancer with mifepristone (MF) have failed, despite in vitro findings on its strong progesterone (P4) antagonist function. Methods: Ovarian cancer human and murine cell lines, cultured high-grade human primary epithelial ovarian cancer (HG-hOEC) cells and their explants; as well as in vivo transgenic mice possessing ovarian cancer were used to assess the molecular mechanism underlying mifepristone (MF) agonistic actions in ovarian cancer progression. Findings: Herein, we show that ovarian cancer cells express traceable/no nuclear P4 receptor (PGR), but abun- dantly P4 receptor membrane component 1 (PGRMC1). MF significantly stimulated ovarian cancer cell migration, proliferation and growth in vivo, and the translocation of PGRMC1 into the nucleus of cancer cells; the effects inhibited by PGRMC1 inhibitor. The beneficial antitumor effect of high-doses MF could not be achieved in human cancer tissue, and the low tissue concentrations achieved with the therapeutic doses only promoted the growth of ovarian cancers. Interpretation: Our results indicate that treatment of ovarian cancer with MF and P4 may induce similar adverse agonistic effects in the absence of classical nuclear PGRs in ovarian cancer. The blockage of PGRMC1 activity may provide a novel treatment strategy for ovarian cancer. Fund: This work was supported by grants from the National Science Centre, Poland (2013/09/N/NZ5/01831 to DP-T; 2012/05/B/NZ5/01867 to MC), Academy of Finland (254366 to NAR), Moikoinen Cancer Research Founda- tion (to NAR) and EU PARP Cluster grant (UDA-POIG.05.01.00-005/12-00/NCREMFP to SW). © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Ovarian cancer Mifepristone Progesterone Nuclear progesterone receptors Progesterone receptor membrane component 1 EBioMedicine 47 (2019) 170–183 Abbreviations: 22-hydroxy MF, (11β,17β)-11-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxy-1-propyn-1-yl)-estra-4,9-dien-3-one; AG-205, inhibitor PGRMC1; DXM, dexamethasone; Di-demethyl MF, (11β,17β)-11-(4-Aminophenyl)-17-hydroxy-17-(1-propyn-1-yl)-estra-4,9-dien-3-one; FSH, follicle-stimulating hormone; GCT, granulosa cell tumor; GR, glucocorticoid receptor; HG, high-grade; HMGB1, high mobility group box 1 protein; hOEC, human ovarian epithelial cancer; HSP90i, GR inhibitor; Inhα/Tag, transgenic mice expressing Simian Virus 40 T antigen under inhibin-α promoter; KK-1, immortalized cell line from Inhα/Tag TG mice; LG, low grade; LH, luteinizing hormone; MF, mifepristone; N-demethyl MF, (11β,17β)-17-Hydroxy-11-[4-(methylamino)phenyl]-17-(1-propyn-1-yl)-estra-4,9-dien-3-one; P4, progesterone; PGR, nuclear progesterone receptors; PGRMC1, pro- gesterone receptor membrane component 1; PR, progesterone receptors; SKOV3, human ovarian cancer cell line with epithelial-like morphology; SPRM, selective progesterone receptor modulator; TG, transgenic; TGF-β1, transforming growth factor β1. ⁎ Corresponding author at: Institute of Biomedicine, University of Turku, Finland. E-mail address: nafis.rahman@utu.fi (N.A. Rahman). https://doi.org/10.1016/j.ebiom.2019.08.035 2352-3964/© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents lists available at ScienceDirect EBioMedicine journal homepage: www.ebiomedicine.com