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Cell Motility and Cancer
Open AccessArticle

Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice

1
Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn, Poland
2
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology University of Turku, 20520 Turku, Finland
3
Department of Medical Pathomorphology, Medical University of Bialystok, 15-269 Bialystok, Poland
4
College of Biological Sciences and Technology, Beijing Forestry University, Beijing 100083, China
5
State Key Laboratory of the Agro-Biotechnology, College of Horticultural Science, China Agricultural University, Beijing 100193, China
6
Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, 15-276 Bialystok, Poland
7
Department of Pediatrics, Turku University Hospital, 20520 Turku, Finland
8
Institute of Reproductive and Developmental Biology, Imperial College London, London W12 0NN, UK
*
Author to whom correspondence should be addressed.
Equally contributed.
Cancers 2020, 12(11), 3263; https://doi.org/10.3390/cancers12113263
Received: 9 September 2020 / Revised: 27 October 2020 / Accepted: 2 November 2020 / Published: 4 November 2020
(This article belongs to the Special Issue Cell Motility and Cancer)
Recently, the antiprogestin activity of selective progesterone receptor (PR) modulator mifepristone (MF) has proven unsuccessful as a potential anti-cancer agent in various clinical trials. Herein, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-α promoter-driven SV40 T-antigen), as well as on the proliferation of two Leydig tumor cell lines. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Only the abundant membrane Pgrmc1 expression was found in LCTs, but no other classical Pgr or nonclassical membrane PRs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Our findings provide novel information that the use of MF as an anti-cancer agent should be considered with caution due to its potential PGRMC1 tumor-promoting pathway activation in cancers.
The selective progesterone receptor modulator mifepristone (MF) may act as a potent antiproliferative agent in different steroid-dependent cancers due to its strong antagonistic effect on the nuclear progesterone receptor (PGR). Hereby, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-α promoter-driven SV40 T-antigen), as well as on LCT (BLTK-1 and mLTC-1) cell proliferation. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Traceable/absent classical Pgr or nonclassical membrane PRs α, β, γ and Pgrmc2, but abundant membrane Pgrmc1 expression, was found in LCTs. MF did not activate glucocorticoid or androgen receptors in LCTs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Accordingly, MF and P4 induced PGRMC1 translocation into the nucleus and thereby stimulated the release of TGFβ1 in LCT cells. MF and P4 treatments upregulated Tgfbr1, Tgfbr2, and Alk1 expression and stimulated TGFβ1 release in LCT cells. Our findings provide novel mechanistic insights into the action of MF as a membrane PR agonist that promotes LCT growth through PGRMC1 and the alternative TGFβ1 signaling pathway. View Full-Text
Keywords: leydig cell tumor; mifepristone; progesterone; progesterone receptors; TGFβ; PGRMC1 leydig cell tumor; mifepristone; progesterone; progesterone receptors; TGFβ; PGRMC1
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Ponikwicka-Tyszko, D.; Chrusciel, M.; Pulawska, K.; Bernaczyk, P.; Sztachelska, M.; Guo, P.; Li, X.; Toppari, J.; Huhtaniemi, I.T.; Wołczyński, S.; Rahman, N.A. Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice. Cancers 2020, 12, 3263.

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