Anticancer research · 2025
Activation of the γ-Aminobutyric Acid Receptor Type B Suppresses the Proliferation of Lung Adenocarcinoma Cells.
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Zhou Yubin, Khawkhiaw Kullanat, Thithuan Kanyarat, Saengboonmee Charupong
Аннотация
BACKGROUND/AIM: The roles of γ-aminobutyric acid (GABA) and its receptors in lung cancer development and progression remain controversial. This study aimed to investigate the effects of activating GABA receptor type B (GABA-B receptor) using baclofen, a GABA-B receptor agonist, on the proliferation of lung adenocarcinoma cells and its underlying mechanisms.
MATERIALS AND METHODS: Differential expression of GABA-B receptors was analyzed using the online Gene Expression Profiling Interactive Analysis tool. Lung adenocarcinoma cell lines, A549 and PC-9, were cultured in RPMI-1640 medium and used for in vitro experiments. Effects of baclofen on cancer cell proliferation were determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Mechanisms of how baclofen inhibits cell proliferation were determined using flow cytometry and western blots.
RESULTS: The expression of GABA-B1 receptor was down-regulated in lung adenocarcinoma compared with normal lung tissues, while GABA-B2 receptor expression was not different between cancer and normal samples. Baclofen significantly inhibited the proliferation of lung adenocarcinoma cells in a dose-dependent manner in both cell lines. Flow cytometry suggested that cancer cells were arrested at the G1 phase of the cell cycle after being treated with baclofen. Thus, the expression of proteins of the G1 cell cycle machinery, namely cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 4, and CDK6, were significantly suppressed. The phosphorylation of CDK2 was also suppressed after baclofen treatment. Moreover, baclofen treatment increased phosphorylated glycogen synthase kinase 3 (GSK3) levels, suggesting inhibition of carcinogenic GSK3 signaling pathway in lung adenocarcinoma.
CONCLUSION: GABA-B1 receptors were down-regulated in lung adenocarcinoma cells. Non-specific activation of the GABA-B receptor by baclofen significantly inhibited lung adenocarcinoma cell proliferation by cell cycle arrest and suppressed the GSK3 signaling pathway.
MATERIALS AND METHODS: Differential expression of GABA-B receptors was analyzed using the online Gene Expression Profiling Interactive Analysis tool. Lung adenocarcinoma cell lines, A549 and PC-9, were cultured in RPMI-1640 medium and used for in vitro experiments. Effects of baclofen on cancer cell proliferation were determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Mechanisms of how baclofen inhibits cell proliferation were determined using flow cytometry and western blots.
RESULTS: The expression of GABA-B1 receptor was down-regulated in lung adenocarcinoma compared with normal lung tissues, while GABA-B2 receptor expression was not different between cancer and normal samples. Baclofen significantly inhibited the proliferation of lung adenocarcinoma cells in a dose-dependent manner in both cell lines. Flow cytometry suggested that cancer cells were arrested at the G1 phase of the cell cycle after being treated with baclofen. Thus, the expression of proteins of the G1 cell cycle machinery, namely cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 4, and CDK6, were significantly suppressed. The phosphorylation of CDK2 was also suppressed after baclofen treatment. Moreover, baclofen treatment increased phosphorylated glycogen synthase kinase 3 (GSK3) levels, suggesting inhibition of carcinogenic GSK3 signaling pathway in lung adenocarcinoma.
CONCLUSION: GABA-B1 receptors were down-regulated in lung adenocarcinoma cells. Non-specific activation of the GABA-B receptor by baclofen significantly inhibited lung adenocarcinoma cell proliferation by cell cycle arrest and suppressed the GSK3 signaling pathway.