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Published on: October 20, 2016
Baclofen Inhibits Glioma Proliferation via the MEK/ERK/CREB Pathway
Boqi Zhou1,2,3, Liping Shen2,3, Xiaojie Lu1,2,3
1Wuxi School of Medicine, Jiangnan University, Wuxi, China.
Abstract:
Objectives: Gamma-aminobutyric acid type B (GABAB) receptors are involved in tumor progression, and baclofen exerts broad-spectrum antitumor effects in various cancers. Nevertheless, its specific function and underlying molecular mechanisms in glioma are still largely unclear. This study aimed to evaluate the effects of baclofen on glioma cells and elucidate the associated signaling pathways. Methods: The antitumor effects of baclofen were evaluated in glioma cell lines, and its underlying molecular mechanisms were explored using transcriptome sequencing integrated with Western blotting. The in vivo antitumor efficacy of baclofen was further verified in animal models. Results: In vitro functional assays revealed that baclofen inhibits the proliferation, migration, and invasion of glioma cells in a dose-dependent manner. Transcriptomic sequencing combined with Western blot validation demonstrated that these effects may be mediated by GABAB receptors, leading to suppressed phosphorylation of key molecules in the Mitogen-activated protein kinase kinase (MEK)/Extracellular regulated protein kinases (ERK) pathway, and consequently reduced phosphorylation of the downstream transcription factors cAMP-response element binding protein (CREB) and Fos Proto-Oncogene (FOS). Furthermore, baclofen regulates the epithelial-mesenchymal transition (EMT-like) program. All these effects were abolished by co-treatment with the specific GABAB antagonist CGP35348. In vivo experiments using a subcutaneous glioma xenograft model further verified that the continuous use of baclofen in experimental animals also demonstrated certain anti-tumor effects. Conclusion: Collectively, these findings demonstrate that baclofen exerts anti-glioma effects through GABAB receptor-mediated inhibition of the MEK/ERK/CREB signaling axis and modulation of the EMT-like pathway, thereby highlighting the potential of baclofen as a therapeutic agent for glioma.
Insights
Baclofen, a GABAB receptor agonist, inhibits glioma cell growth, migration, and invasion. It targets the MEK/ERK/CREB pathway and epithelial-mesenchymal transition, showing therapeutic potential for glioma treatment.
Area of Science:
- Neuroscience
- Oncology
- Molecular Biology
Background:
- Gamma-aminobutyric acid type B (GABAB) receptors are implicated in cancer progression.
- Baclofen exhibits antitumor properties across various cancer types.
- The precise role and mechanisms of baclofen in glioma remain under investigation.
Purpose of the Study:
- To investigate the anti-glioma effects of baclofen.
- To elucidate the molecular pathways targeted by baclofen in glioma cells.
Main Methods:
- In vitro studies using glioma cell lines to assess baclofen's impact on proliferation, migration, and invasion.
- Transcriptome sequencing and Western blotting to identify molecular mechanisms.
- In vivo validation using a subcutaneous glioma xenograft model.
Main Results:
- Baclofen dose-dependently inhibited glioma cell proliferation, migration, and invasion.
- Baclofen suppressed phosphorylation in the MEK/ERK/CREB/FOS signaling pathway via GABAB receptors.
- Baclofen modulated the epithelial-mesenchymal transition (EMT)-like program.
- Effects were reversed by the GABAB antagonist CGP35348.
- In vivo studies confirmed baclofen's anti-glioma efficacy.
Conclusions:
- Baclofen demonstrates anti-glioma activity by inhibiting the GABAB receptor-mediated MEK/ERK/CREB signaling axis.
- Baclofen also modulates the EMT-like pathway, contributing to its anti-tumor effects.
- These findings suggest baclofen as a potential therapeutic agent for glioma.
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