High Levels of Progesterone Receptor B in MCF-7 Cells Enable Radical Anti-Tumoral and Anti-Estrogenic Effect of Progestin

Abstract

The widely reported conflicting effects of progestin on breast cancer suggest that the progesterone receptor (PR) has dual functions depending on the cellular context. Cell models that enable PR to fully express anti-tumoral properties are valuable for the understanding of molecular determinant(s) of the anti-tumoral property. This study evaluated whether the expression of high levels of PR in MCF-7 cells enabled a strong anti-tumoral response to progestin. MCF-7 cells were engineered to overexpress PRB by stable transfection. A single dose of Promegestone (R5020) induced an irreversible cell growth arrest and senescence-associated secretory phenotype in MCF-7 cells with PRB overexpression (MCF-7PRB cells) but had no effect on MCF-7 cells with PRA overexpression. The growth-arresting effect was associated with downregulations of cyclin A2 and B1, CDK2, and CDK4 despite an initial upregulation of cyclin A2 and B1. R5020 also induced an evident activation of Nuclear Factor κB (NF-κB) and upregulation of interleukins IL-1α, IL-1β, and IL-8. Although R5020 caused a significant increase of CD24+CD44+ cell population, R5020-treated MCF-7PRB cells were unable to form tumorspheres and underwent massive apoptosis, which is paradoxically associated with marked downregulations of the pro-apoptotic proteins BID, BAX, PARP, and Caspases 7 and 8, as well as diminution of anti-apoptotic protein BCL-2. Importantly, R5020-activated PRB abolished the effect of estrogen. This intense anti-estrogenic effect was mediated by marked downregulation of ERα and pioneer factor FOXA1, leading to diminished chromatin-associated ERα and FOXA1 and estrogen-induced target gene expression. In conclusion, high levels of agonist-activated PRB in breast cancer cells can be strongly anti-tumoral and anti-estrogenic despite the initial unproductive cell cycle acceleration. Repression of ERα and FOXA1 expression is a major mechanism for the strong anti-estrogenic effect.

Possible Participation of Adenine Nucleotide Translocase ANT1 in the Cytotoxic Action of Progestins, Glucocorticoids, and Diclofenac on Tumor Cells

“…The MCF-7 cell line is sensitive to progestins: P 4 was shown to inhibit the proliferation of these cells with an IC 50 value of 6.5 ± 0.2 μM [ 42 ]. The anticancer action of progestins is known to be realized via the membrane and nuclear progesterone receptors (PR) [ 43 ]. Since all the drugs tested downregulated the ANT1 expression in MCF-7, it can be assumed that ANT1 downregulation in PR-positive cells can lead to cell death.…”

“…To evaluate the participation of ANT1 in the regulation of cell viability by steroid hormones and DCF, we examined their effect on the viability and ANT1 expression in cancerous cell lines sensitive to steroid hormones. As is known, all the cell lines, HeLa [ 46 ], MCF-7 [ 43 ], Hep-2 [ 47 ], and K-562 [ 48 ], contain steroid hormone receptors. It is known that PR and GR are expressed in the lung fibroblasts [ 49 ]; however, information about the expression of PR or GR in the Wi-38 cell line is not available.…”

Anti-collagenase, Anti-elastase, Anti-urease, and Anti-cancer Potentials of Isokaempferide as Natural Compound: <i>In vitro</i> and <i>in silico</i> Study

“…The surface receptors with high expression in the mentioned cell lines were also evaluated using molecular docking. EGFR (PDB ID: 5WB7) 21) was chosen for SPC-A-1 22) , estrogen receptor (PDB ID: 3OS8) was chosen for SK-LU-1 cells 23) , CD47 (PDB ID: 2JJS) 24) was chosen for 95D 25) , progesterone receptor (PDB ID: 1A28) was chosen for MCF7 26) , folate receptor (PDB ID: 4LRH) was chosen for Hs 578Bst 27) , CD44 (PDB ID: 4PZ3) 28) was chosen for Hs 319.T 27) , HER2 (PDB ID: 1N8Z) 29) was chosen UACC-3133 30) , CD155 (PDB ID: 3URO) 31) was chosen for CL40 32) , CXCR4 (PDB ID: 3ODU) 33) was selected for SW1417 34) , CD97 (PDB ID: 7DO4) 35) was selected for LS1034 36) , and endothelin receptor (PDB ID: 5X93) 37) was selected for SW480 38) . The chemical activities of isokaempferide were estimated against these enzymes and proteins.…”

Mechanisms of Senescence in Cancer: Positive and Negative Aspects of Cancer Cells Senescence

“…However, progesterone-induced replicative senescence through β-gal activity, particularly PRA presence, but to a much lesser extent by PRB [204]. Bajalovic et al (2022) observed the opposite effect after treating breast cancer MCF-7 cells in the synthetic form of progesterone-progestin (R5020). These synthetic hormones induced replicative senescence in MCF-7, expressing high levels of PRB.…”

“…R5020 in MCF-7 caused a reduction in CDK2 and CDK4 and decreased in S phase cells. Progestin in MCF-7PRB cells activated the NF-κB pathway by phosphorylating IκBα and p65 pathways, leading to increased expression of SASP, such as IL-1a, IL-1b, and IL-8 [205]. Another synthetic form of progesterone is megestrol acetate.…”