Dong Jing, Wu Yuanyuan, Che Ji, He Zhiyong, Zhang Jun
Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cancer Metab. 2025 Jun 23;13(1):33. doi: 10.1186/s40170-025-00403-4.
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.
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.
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.
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.
癌细胞对谷氨酰胺表现出异常依赖，这与促进肿瘤生长的γ-氨基丁酸（GABA）代谢途径的过度激活有关。据报道，α2-肾上腺素能受体激动剂右美托咪定（DEX）可促进结直肠癌（CRC）进展。然而，GABA能信号在DEX诱导的肿瘤发生中的作用仍不清楚。
本研究分析了临床CRC标本和癌症基因组图谱（TCGA），以评估GABAB受体亚基1（GABBR1）的表达及其预后相关性。我们使用酶联免疫吸附测定（ELISA）测量神经递质水平，并通过蛋白质免疫印迹法评估CRC细胞系（RKO和SW480）中谷氨酰胺酶1（GLS1）、谷氨酸脱羧酶1（GAD1）、GABBR1及其亚基GB1e的表达。通过Ki67免疫荧光、伤口愈合和Transwell实验评估细胞增殖、迁移和侵袭。进行体内实验以评估DEX对CRC异种移植模型中肿瘤生长的影响。
结果显示，人CRC组织中GABBR1表达显著增加。DEX以剂量依赖的方式上调GLS1和GAD1表达，同时还促进CRC细胞系中GABA释放和GB1e表达。DEX激活的GABA能信号增强了CRC细胞增殖、迁移和侵袭，以及体内肿瘤生长。机制上，上调的GB1e通过抑制Tyr216-p-GSK3β活性稳定β-连环蛋白表达，从而促进上皮-间质转化（EMT）过程。
我们的研究表明，DEX显著增加CRC细胞中GABA释放和GB1e表达，导致GSK3β/β-连环蛋白途径激活，进而引发EMT。这些发现表明，GABA能信号可能有助于DEX诱导的促肿瘤作用。
