Cancer & Metabolism (Jun 2025)
Dexmedetomidine promotes colorectal cancer progression mediated by gamma-aminobutyric acid signaling
Abstract
Abstract Objective Cancer cells exhibit abnormal dependence on glutamine, which is associated with the hyperactivation of γ-aminobutyric acid (GABA) metabolic pathways that promotes tumor growth. The α2-adrenergic receptor agonist dexmedetomidine (DEX) has been reported to promote colorectal cancers (CRC) progression. However, the role of GABAergic signaling in DEX-induced tumorigenesis remains unclear. Methods This study analyzed clinical CRC specimens and The Cancer Genome Atlas (TCGA) to assess the expression of GABAB receptor subunit 1 (GABBR1) and its prognostic relevance. We measured neurotransmitter levels using ELISA and evaluated the expression of glutaminase 1 (GLS1), glutamate decarboxylase 1 (GAD1), GABBR1, and its subunit GB1e in CRC cell lines (RKO and SW480) using Western blotting. Cell proliferation, migration, and invasion were evaluated through Ki67 immunofluorescence, wound healing, and transwell assays. In vivo experiments were performed to evaluate the effect of DEX on tumor growth in CRC xenograft models. Results The results revealed a significant increase in GABBR1 expression in human CRC tissues. DEX upregulated GLS1 and GAD1 expression in a dose-dependent manner, while also promoted GABA release and GB1e expression in CRC cell lines. Activated GABAergic signaling by DEX enhanced CRC cell proliferation, migration, and invasion, as well as tumor growth in vivo. Mechanistically, upregulated GB1e stabilized β-catenin expression by inhibiting Tyr216-p-GSK3β activity, thereby facilitating the epithelial-mesenchymal transition (EMT) process. Conclusion Our study demonstrated that DEX significantly increased GABA release and GB1e expression in CRC cells, leading to activation of GSK3β/β-catenin pathway and then EMT. These findings suggest that GABAergic signaling may contribute to DEX-induced tumor-promoting effects.
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