The Interplay of GPER1 with 17β-Aminoestrogens in the Regulation of the Proliferation of Cervical and Breast Cancer Cells: A Pharmacological Approach

Mariana Segovia-Mendoza (), Elahe Mirzaei, Heriberto Prado-Garcia, Luis D. Miranda, Alejandra Figueroa and Cristina Lemini ()
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Mariana Segovia-Mendoza: Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Ciudad Universitaria, Ciudad de México 04510, Mexico
Elahe Mirzaei: Instituto Nacional de Medicina Genómica, Col. Arenal Tepepan, Ciudad de México 14610, Mexico
Heriberto Prado-Garcia: Laboratorio de Onco-Inmunobiologia, Departamento de Enfermedades Crónico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Calzada de Tlalpan 4502, Col. Sección XVI, Ciudad de México 14080, Mexico
Luis D. Miranda: Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S.N., Ciudad Universitaria, Ciudad de México 04510, Mexico
Alejandra Figueroa: Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Ciudad Universitaria, Ciudad de México 04510, Mexico
Cristina Lemini: Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Ciudad Universitaria, Ciudad de México 04510, Mexico

IJERPH, 2022, vol. 19, issue 19, 1-19

Abstract: The G-protein-coupled receptor for estrogen (GPER1) is a transmembrane receptor involved in the progression and development of various neoplasms whose ligand is estradiol (E2). 17β-aminoestrogens (17β-AEs) compounds, analogs to E2, are possible candidates for use in hormone replacement therapy (HRT), but our knowledge of their pharmacological profile is limited. Thus, we explored the molecular recognition of GPER1 with different synthetic 17β-AEs: prolame, butolame, and pentolame. We compared the structure and ligand recognition sites previously reported for a specific agonist (G1), antagonists (G15 and G36), and the natural ligand (E2). Then, the biological effects of 17β-AEs were analyzed through cell viability and cell-cycle assays in two types of female cancer. In addition, the effect of 17β-AEs on the phosphorylation of the oncoprotein c-fos was evaluated, because this molecule is modulated by GPER1. Molecular docking analysis showed that 17β-AEs interacted with GPER1, suggesting that prolame joins GPER1 in a hydrophobic cavity, similarly to G1, G15, and E2. Prolame induced cell proliferation in breast (MCF-7) and cervical cancer (SIHA) cells; meanwhile, butolame and pentolame did not affect cell proliferation. Neither 17β-AEs nor E2 changed the activation of c-fos in MCF-7 cells. Meanwhile, in SIHA cells, E2 and 17β-AEs reduced c-fos phosphorylation. Thus, our data suggest that butolame and pentolame, but not prolame, could be used for HRT without presenting a potential risk of inducing breast- or cervical-cancer-cell proliferation. The novelty of this work lies in its study of compound analogs to E2 that may represent important therapeutic strategies for women in menopause, with non-significant effects on the cell viability of cancer cells. The research focused on the interactions of GPER1, a molecule recently associated with promoting and maintaining various neoplasms.

Keywords: G-protein-coupled estrogen receptor (GPER1); 17?-aminoestrogens (17?-AEs); molecular docking; cell viability; cancer cells (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2022
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