In vitro and in silico investigation of the critical role of GABAB receptor activation in human breast cancer and its natural agonists

Ali,Mustafa Hussein; Muhseen,Ziyad Tariq; Al-Hajjaj,Zahraa Yousif; Al-Ghanimi,Hussein Hazim; Alshammari,Abdulrahman; Albekairi,Norah Abdullah

doi:10.3892/ol.2025.15103

In vitro and in silico investigation of the critical role of GABA_B receptor activation in human breast cancer and its natural agonists

Authors:
- Mustafa Hussein Ali
- Ziyad Tariq Muhseen
- Zahraa Yousif Al-Hajjaj
- Hussein Hazim Al-Ghanimi
- Abdulrahman Alshammari
- Norah Abdullah Albekairi
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Affiliations: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, P.R. China, Department of Molecular Biology, Iraqi Center for Cancer and Medical Genetic Research, Mustansiriyah University, Baghdad 10064, Iraq, Department of Anesthesia Techniques and Intensive Care, Al Taff University College, Karbala 56001, Iraq, Department of Biomedical Engineering, College of Engineering, University of Warith Al-Anbiyaa, Karbala 56001, Iraq, Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Published online on: May 21, 2025 https://doi.org/10.3892/ol.2025.15103
Article Number: 357
Copyright: © Ali et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

γ‑aminobutyric acid type B (GABA_B) receptors, a class of G protein‑coupled receptors, serve pivotal roles in modulating cellular signaling pathways across both neural and peripheral tissues, although their underlying mechanisms involved in cancer progression have yet to be fully elucidated. The aim of the present study was to investigate the effect of GABA_B receptor activation on the migration, invasion, clonogenicity, proliferation and epithelial‑mesenchymal transition (EMT) of the MDA‑MB‑231 human breast cancer cell line. To meet this aim, MDA‑MB‑231 cells were treated with various concentrations of the GABA_B receptor agonist, baclofen. Treatment with baclofen caused a significant inhibition of cell migration, invasion and clonogenicity in a dose‑dependent manner. Moreover, baclofen treatment led to a downregulation of vimentin expression, whereas the expression of β‑catenin was upregulated, indicating suppression of EMT in MDA‑MB‑231 cells. Notably, the phosphorylation levels of Akt and ERK1/2 remained unaltered, suggesting that the inhibitory effects mediated by baclofen on EMT were not mediated via either the phosphoinositide 3‑kinase/Akt or the MAPK pathways. To identify potential natural GABA_B receptor agonists, molecular docking techniques were employed using the MPD3 database. This in silico approach revealed three compounds (PubChem identification, 450432, 6448 and 6057) as promising candidates, which all exhibited critical hydrogenbond interactions with the GABAB receptorbinding site. These compounds may serve as lead compounds for developing novel, naturally derived GABA_B receptor agonists. Taken together, the findings demonstrated that GABA_B receptor activation via baclofen inhibits multiple aggressive phenotypes in MDA‑MB‑231 breast cancer cells. Moreover, these results offer promising avenues for developing GABA_B receptor agonists as a therapeutic strategy in breast cancer treatment.

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