Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice

Abstract

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.

Comprehensive and Quantitative Analysis of the Changes in Proteomic and Phosphoproteomic Profiles during Stimulation and Repression of Steroidogenesis in MA-10 Leydig Cells

“…The PGRMC2 protein also exhibited increased phosphorylation in the MA-10 Leydig cells treated with Fsk+AICAR vs. controls. PGRMC2 is a membrane-associated progesterone receptor (MAPR) present in Leydig cells and is believed to play a role in the progesterone auto/paracrine action on Leydig cells [ 55 , 56 ] in addition to potentially regulating the activity of some cytochrome P450 enzymes [ 57 ]. We showed that PGRMC2 is present in MA-10 Leydig cells and that it is phosphorylated after AMPK activation.…”

Quo vadis PGRMC? Grand-Scale Biology in Human Health and Disease

“…Rahman and colleagues showed that mifepristone also influences PGRMC1 signaling. For ovarian [38] and testicular [39] cancer models mifepristone leads to PGRMC1 translocation to the nucleus which is associated with altered gene expression, increased proliferation, migration, and invasiveness in mouse xenograft tumor models. PGRMC1 post-translational modifications were not examined, but Sabbir's findings would predict that mifepristone affects particularly PGRMC1's phosphorylation and sumoylation states.…”

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

“…However, PGRMC1's role in tumor development and progression is not limited to breast cancer. Indeed, several studies reported its involvement also in other hormone-sensitive cancers, including testicular Leydig cell tumor proliferation and invasion through Transforming Growth Factor beta (TGF-β) alternative pathway [169], endometrial cancer [170] and ovarian cancer, in which PGRMC1 activation promotes cell viability, growth, proliferation, migration and survival through PI3K/Akt-mediated inhibition of apoptosis [171,172] (Figure 4). PGRMC2 is a membrane-bound receptor structurally similar to PGRMC1, although it displays a different N-terminal transmembrane domain and is less functionally characterized [173].…”