Identification of a human estrogen receptor α tetrapeptidic fragment with dual antiproliferative and anti-nociceptive action.

Autor: Jouffre B; NEURO-DOL Basics and Clinical Pharmacology of Pain, INSERM - UMR 1107, University of Clermont Auvergne, 63000, Clermont-Ferrand, France.; Faculty of Medicine, ANALGESIA Institute, 63000, Clermont-Ferrand, France., Acramel A; CiTCoM, CNRS - UMR 8038, INSERM 1268, Faculty of Pharmacy of Paris, University of Paris Cité, 75270, Paris Cedex 06, France.; Department of Pharmacy, Institut Curie, 75248, Paris, Cedex 05, France., Belnou M; Laboratoire des Biomolécules (LBM), CNRS - UMR 7203, Sorbonne Université, Ecole Normale Supérieure, PSL Research University, 75252, Paris Cedex 05, France., Santolla MF; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy., Talia M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy., Lappano R; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy., Nemati F; Preclinical Investigation Laboratory (LIP), Department of Translational Research, Institut Curie, PSL Research University, 75248, Paris Cedex 05, France., Decaudin D; Preclinical Investigation Laboratory (LIP), Department of Translational Research, Institut Curie, PSL Research University, 75248, Paris Cedex 05, France.; Department of Medical Oncology, Institut Curie, 75248, Paris Cedex 05, France., Khemtemourian L; Laboratoire des Biomolécules (LBM), CNRS - UMR 7203, Sorbonne Université, Ecole Normale Supérieure, PSL Research University, 75252, Paris Cedex 05, France.; Institute of Chemistry and Biology of Membranes and Nanoobjects (CBMN), CNRS - UMR 5248, Institut Polytechnique Bordeaux, University of Bordeaux, 33600, Pessac, France., Liu WQ; CiTCoM, CNRS - UMR 8038, INSERM 1268, Faculty of Pharmacy of Paris, University of Paris Cité, 75270, Paris Cedex 06, France., Maggiolini M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy., Eschalier A; NEURO-DOL Basics and Clinical Pharmacology of Pain, INSERM - UMR 1107, University of Clermont Auvergne, 63000, Clermont-Ferrand, France.; Faculty of Medicine, ANALGESIA Institute, 63000, Clermont-Ferrand, France., Mallet C; NEURO-DOL Basics and Clinical Pharmacology of Pain, INSERM - UMR 1107, University of Clermont Auvergne, 63000, Clermont-Ferrand, France.; Faculty of Medicine, ANALGESIA Institute, 63000, Clermont-Ferrand, France., Jacquot Y; CiTCoM, CNRS - UMR 8038, INSERM 1268, Faculty of Pharmacy of Paris, University of Paris Cité, 75270, Paris Cedex 06, France. yves.jacquot@u-paris.fr.; Laboratoire des Biomolécules (LBM), CNRS - UMR 7203, Sorbonne Université, Ecole Normale Supérieure, PSL Research University, 75252, Paris Cedex 05, France. yves.jacquot@u-paris.fr.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Jan 24; Vol. 13 (1), pp. 1326. Date of Electronic Publication: 2023 Jan 24.
DOI: 10.1038/s41598-023-28062-9
Abstrakt: The synthetic peptide ERα17p (sequence: PLMIKRSKKNSLALSLT), which corresponds to the 295-311 region of the human estrogen receptor α (ERα), induces apoptosis in breast cancer cells. In mice and at low doses, it promotes not only the decrease of the size of xenografted triple-negative human breast tumors, but also anti-inflammatory and anti-nociceptive effects. Recently, we have shown that these effects were due to its interaction with the seven-transmembrane G protein-coupled estrogen receptor GPER. Following modeling studies, the C-terminus of this peptide (sequence: NSLALSLT) remains compacted at the entrance of the GPER ligand-binding pocket, whereas its N-terminus (sequence: PLMI) engulfs in the depth of the same pocket. Thus, we have hypothesized that the PLMI motif could support the pharmacological actions of ERα17p. Here, we show that the PLMI peptide is, indeed, responsible for the GPER-dependent antiproliferative and anti-nociceptive effects of ERα17p. By using different biophysical approaches, we demonstrate that the NSLALSLT part of ERα17p is responsible for aggregation. Overall, the tetrapeptide PLMI, which supports the action of the parent peptide ERα17p, should be considered as a hit for the synthesis of new GPER modulators with dual antiproliferative and anti-nociceptive actions. This study highlights also the interest to modulate GPER for the control of pain.
(© 2023. The Author(s).)
Databáze: MEDLINE
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