Abstract
Several signaling pathways are aberrantly activated in head and neck squamous cell carcinoma (HNSCC), including the Hedgehog-Gli (HH-GLI), WNT, EGFR, and NOTCH pathways. The HH-GLI pathway has mostly been investigated in the context of canonical signal transduction and the inhibition of the membrane components of the pathway. In this work we investigated the role of downstream inhibitors GANT61 and lithium chloride (LiCl) on cell viability, wound closure, and colony forming ability of HNSCC cell lines. Five HNSCC cell lines were treated with HH-GLI pathway inhibitors affecting different levels of signal transduction. GANT61 and LiCl reduce the proliferation and colony formation capabilities of HNSCC cell lines, and LiCl has an additional effect on wound closure. The major effector of the HH-GLI signaling pathway in HNSCC is the GLI3 protein, which is expressed in its full-length form and is functionally regulated by GSK3β. LiCl treatment increases the inhibitory Ser9 phosphorylation of the GSK3β protein, leading to increased processing of GLI3 from full-length to repressor form, thus inhibiting HH-GLI pathway activity. Therefore, downstream inhibition of HH-GLI signaling may be a promising therapeutic strategy for HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) encompasses tumors arising in the oral cavity, larynx, nasopharynx, oropharynx, hypopharynx, and salivary glands, with an annual incidence of around 880,000 new cases worldwide and around 450,000 deaths [1]
We focused our research on two inhibitors, a direct glioma-associated oncogene homolog (GLI) inhibitor GANT61, and lithium chloride (LiCl), a GSK3β inhibitor
The effect we detected for LiCl treatments seems to work in the opposite manner: LiCl leads to phosphorylation of GSK3β at Ser9, leading to increased processing of GLI3FL to GLIR
Summary
Head and neck squamous cell carcinoma (HNSCC) encompasses tumors arising in the oral cavity, larynx, nasopharynx, oropharynx, hypopharynx, and salivary glands, with an annual incidence of around 880,000 new cases worldwide and around 450,000 deaths [1]. Major risk factors are tobacco and alcohol consumption and occupational risks (exposure to wood dust, acid mist, asbestos or solvents in the textile and wood industry) [3]. In Croatia, the majority of HNSCC cases are still HPV-negative and are associated with tobacco and alcohol consumption [6,7]. In HNSCC, cancer stem cells (CSC) are considered to be responsible for tumor initiation, progression, and metastasis, and for drug resistance and recurrence. To bypass potential tumor resistance, other potential molecular targets are being investigated, such as the phosphoinositol 3 kinase (PI3K) pathway, human growth hormone (HGF) pathway, NOTCH signaling pathway, HH-GLI signaling pathway, and angiogenesis regulated by vascular endothelial growth factor (VEGF) signaling [10]
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