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<p>Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Glutamate decarboxylase 1 (GAD1), which mainly produces gamma-aminobutyric acid (GABA) in neurons, has also been implicated in tumor progression. However, the role of GAD1 in glioma is not well understood. Our study found that GAD1 expression is downregulated in glioma, correlating with poor prognosis in glioma patients. Overexpression of GAD1 suppressed glioblastoma cell proliferation, colony formation, cell cycle progression, migration, and invasion, whereas knockdown of GAD1 promoted these phenotypes. Furthermore, GAD1 overexpression significantly reduced the protein levels of p-GSK3β (ser9) and β-catenin, as well as the downstream molecules Cyclin D1 and MMP9, whereas GAD1 knockdown increased their expression. The GSK3β inhibitor AR-A014418 effectively counteracted the effects of GAD1 knockdown, suppressing the enhanced proliferation, cell cycle progression, and invasion of glioblastoma cells, while also reducing the expression of p-GSK3β, β-catenin, Cyclin D1, and MMP9. Furthermore, zebrafish xenotransplantation experiments demonstrated that GAD1 overexpression suppressed tumor growth, whereas GAD1 knockdown facilitated tumor formation. Collectively, these results suggest that GAD1 inhibits the expression of Cyclin D1 and MMP9 via the p-GSK3β/β-catenin pathway, thereby impeding glioblastoma progression. These findings may offer a novel therapeutic target for glioblastoma treatment.</p>

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Glutamate decarboxylase 1 (GAD1) suppresses the progression of glioblastoma through GSK3β/β-catenin pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Yanwen Zheng,
  • Zhaomin Zhong,
  • Chiyu Zhang,
  • Jin Gu

摘要

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Glutamate decarboxylase 1 (GAD1), which mainly produces gamma-aminobutyric acid (GABA) in neurons, has also been implicated in tumor progression. However, the role of GAD1 in glioma is not well understood. Our study found that GAD1 expression is downregulated in glioma, correlating with poor prognosis in glioma patients. Overexpression of GAD1 suppressed glioblastoma cell proliferation, colony formation, cell cycle progression, migration, and invasion, whereas knockdown of GAD1 promoted these phenotypes. Furthermore, GAD1 overexpression significantly reduced the protein levels of p-GSK3β (ser9) and β-catenin, as well as the downstream molecules Cyclin D1 and MMP9, whereas GAD1 knockdown increased their expression. The GSK3β inhibitor AR-A014418 effectively counteracted the effects of GAD1 knockdown, suppressing the enhanced proliferation, cell cycle progression, and invasion of glioblastoma cells, while also reducing the expression of p-GSK3β, β-catenin, Cyclin D1, and MMP9. Furthermore, zebrafish xenotransplantation experiments demonstrated that GAD1 overexpression suppressed tumor growth, whereas GAD1 knockdown facilitated tumor formation. Collectively, these results suggest that GAD1 inhibits the expression of Cyclin D1 and MMP9 via the p-GSK3β/β-catenin pathway, thereby impeding glioblastoma progression. These findings may offer a novel therapeutic target for glioblastoma treatment.