Chemotherapeutic alteration of β-catenin and c-kit expression by imatinib in p16-positive squamous cell carcinoma compared to HPV-negative HNSCC cells in vitro

Abstract

The most common neoplasm arising in the upper aerodigestive tract is head and neck squamous cell carcinoma (HNSCC). Tumor growth, invasion and systemic dissemination is a multistep process of dysregulated cellular signaling pathways and an altered cell-cell and cell-matrix interaction. Aberrant Wnt/β-catenin signaling is linked to tumor development and dissemination in several tumor entities. β-catenin is a multifunctional protein within the canonical Wnt pathway, which is an important factor for reducing cell-cell adhesion in malignant tissue and for triggering cell cycle progression and unscheduled proliferation. Another pivotal factor in carcinogenesis is the tyrosine kinase receptor c-kit, which in the case of dysregulated expression is associated with neoplastic transformation in epithelial tissue. This study evaluates the expression pattern of secreted and nuclear β-catenin and c-kit in p16-positive and HPV-negative squamous cell carcinomas (SCC) and the vulnerability of therapy with the tyrosine kinase inhibitor imatinib as a potential targeted treatment modality compared to platinum-based chemotherapeutic drugs. The different squamous tumor cell lines were incubated with increasing concentrations of carboplatin (3 or 7.5 μ mol/ml) and imatinib (18 or 30 μ mol/ml). ELISA and immunohistochemical methods were carried out after 48, 72, 120, 192 and 240 h. We detected a reliable trend towards significantly decreased cytosolic and nuclear β-catenin and c-kit expression levels in p16-positive SCC and non-HPV HNSCC cells induced by imatinib exposure for an extended incubation period, whereas platinum-based agents had no or, at best, a slight influence. Virus-transformed squamous cell carcinoma (CERV196) cells were characterized by a reduced susceptibility to an imatinib-altered β-catenin expression. Further studies are planned to investigate this observance in HPV-positive HNSCC in vitro. The implementation of a selective molecular therapy in established chemotherapeutic regimes may enhance the efficacy of platinum-based chemotherapy without increased toxicity and could thus improve the clinical outcome in HNSCC, irrespective of the HPV status.