gant-61 and Mouth-Neoplasms

Due to its importance in the pathogenesis of oral squamous cell carcinoma (OSCC), the Hedgehog (HH) pathway is considered a potential therapeutic target. We investigated the effects of GANT61, a GLI inhibitor, on HH gene expression, as well as on metastatic OSCC cell proliferation and death. Following culture in DMEM medium, cytotoxicity of GANT61 against different tumor and non-tumor cell types was assessed by alamarBlue assays. Cytotoxicity analysis revealed that the metastatic HSC3 cell line was the most sensitive (IC

Topics: Adult; Apoptosis; Carcinoma, Squamous Cell; Cell Proliferation; Cell Survival; Cells, Cultured; Gene Expression Regulation, Neoplastic; Humans; Mouth Neoplasms; Neoplasm Metastasis; Pyridines; Pyrimidines; Zinc Finger Protein GLI1

Aberrant activation of HH/GLI has recently been reported in multiple cancer types, yet its role in oral squamous cell carcinoma (OSCC) has not been investigated. In this study, we aimed to determine the role of HH/GLI in OSCC. Expression of GLI1 and GLI2 was examined in OSCC samples from 136 patients by immunohistochemistry and correlated with clinicopathology parameters and clinical outcomes of the patients. Two HH/GLI specific small molecule inhibitors cyclopamine and GANT61, were used to test the potential role of HH/GLI in OSCC. We found that GLI2, one of the main transcriptional activators of HH/GLI signalling, was expressed in 60 (44%) of the 136 OSCC samples and the expression was significantly associated with poor clinical outcomes. Only 44% of the patients whose tumours expressed GLI2 survived at 5years after surgery compared to 77% of those whose tumours lacked the GLI2 expression (P<0.0001). Both cyclopamine and GANT61 effectively inhibited GLI expression, slowed cell growth, promoted G1 arrest, increased apoptosis and inhibited migration of OSCC cells. Our results demonstrate that activation of HH/GLI pathway plays an important role in OSCC progression. Together with the finding that expression of GLI2 is strongly associated with a poor clinic outcome of OSCC patients, the data suggest that a subset of OSCC patients may benefit from anti-HH/GLI therapies.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Immunohistochemistry; Male; Middle Aged; Molecular Targeted Therapy; Mouth Neoplasms; Neoplasm Proteins; Prognosis; Pyridines; Pyrimidines; Signal Transduction; Transcription Factors; Veratrum Alkaloids; Young Adult; Zinc Finger Protein GLI1