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Inhibition of GSK3α/β impairs the progression of HNSCC
Lisa Schulz1, Ralph Pries1, Aruna Sree Lanka1
1Department of Otorhinolaryngology, University of Luebeck, Luebeck 23538, Germany.
Background:
Head and neck squamous cell cancer (HNSCC) is one of the most common tumors worldwide and there is an enormous need for innovative therapy approaches. Several recent studies suggest tumor entity specific roles of glycogen synthase kinase 3 (GSK3) in different human cancers, acting as tumor suppressor or as tumor promoter. Here we describe the role of GSK3 with respect to different parameters within HNSCC progression.
Methods:
Base line expression and activity profiles of p-GSK3α/β (Ser21/9) and p-GSK3α/β (Tyr279/216) were analyzed by immunohistochemistry and western blotting. Four different permanent HNSCC cell lines were exposed to the potent GSK3α/β inhibitor SB 216763. Cell viability was controlled via the MTT test. Cell migration was quantified with the Real Time Cell Analyzer (RCTA) xCELLigence. Regulation of the epithelial-mesenchymal transition (EMT) was measured with the Human Epithelial to Mesenchymal Transition (EMT) RT2 Profiler™ PCR Array and scratch assays. Taqman probes were used to detect the specific gene expression profiles of inflammatory cytokines Interleukin IL1β, IL6, IL8, IL10, TNFα and IFNβ.
Results:
Exposure of permanent HNSCC cell lines to the specific GSK3α/β inhibitor SB 216763 leads to significant growth inhibition, inhibition of migration and decreased levels of active GSK3α/β in a dose dependent manner.Exposure of HNSCC lines to SB 216763 also resulted in a markable shift of EMT markers and functional EMT dysregulation. Functionally GSK3 differentially mediates the expression of TLR4- and TLR3-induced inflammatory cytokines in HNSCC, whereas no effect of SB 216763 on the NFkB activity was noticed.
Conclusion:
GSK3α/β plays a crucial role in a variety of regulatory networks for HNSCC cancer progression as it drives proliferation or migration and thus GSK3 could serve as an interesting target for clinical drug development.
Insights
Glycogen synthase kinase 3 (GSK3) inhibition significantly reduces head and neck squamous cell cancer (HNSCC) growth and migration. Targeting GSK3 offers a promising therapeutic strategy for HNSCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Head and neck squamous cell cancer (HNSCC) is a prevalent malignancy with a critical need for novel therapies.
- Glycogen synthase kinase 3 (GSK3) has demonstrated varied roles in human cancers, acting as either a tumor suppressor or promoter.
- Understanding GSK3's specific functions in HNSCC progression is essential for developing targeted treatments.
Purpose of the Study:
- To investigate the role of glycogen synthase kinase 3 (GSK3) in the progression of head and neck squamous cell cancer (HNSCC).
- To evaluate the effects of GSK3 inhibition on HNSCC cell viability, migration, and epithelial-mesenchymal transition (EMT).
- To explore GSK3's influence on inflammatory cytokine expression in HNSCC.
Main Methods:
- Analysis of baseline expression and activity of GSK3α/β using immunohistochemistry and western blotting.
- Treatment of HNSCC cell lines with the GSK3α/β inhibitor SB 216763.
- Assessment of cell viability (MTT assay), migration (xCELLigence), EMT markers (PCR Array), and inflammatory cytokine gene expression (Taqman probes).
Main Results:
- GSK3α/β inhibition by SB 216763 resulted in dose-dependent reduction in HNSCC cell growth and migration.
- Inhibition of GSK3α/β led to significant alterations in EMT markers and functional EMT dysregulation.
- GSK3 differentially mediated the expression of TLR4- and TLR3-induced inflammatory cytokines in HNSCC, independent of NFkB activity.
Conclusions:
- GSK3α/β is a critical regulator of proliferation and migration in HNSCC progression.
- GSK3 plays a significant role in various regulatory networks governing HNSCC.
- GSK3 represents a potential therapeutic target for clinical drug development in HNSCC.
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