ABSTRACT
Metastasis is a primary reason related to the mortality of oral squamous cell carcinoma (OSCC) patients. A program called epithelial-mesenchymal transition (EMT) has been shown to play a critical role in promoting metastasis in epithelium-derived carcinoma. During EMT, epithelial cancer cells acquire motile mesenchymal phenotypes and detach from primary tumors. Recent lines of evidence have suggested that EMT confers cancer cells with tumor-initiating ability. Therefore, selective targeting of EMT would lead to the development of effective therapeutic agents. In this study, using a chemical biology approach, we identified isoxsuprine, a ß2-adrenergic receptor (ß2-AR) agonist as a low-molecular-weight compound that interferes with the acquisition of mesenchymal phenotypes of oral cancer cells. Treatment of multiple types of oral cancer cells with isoxsuprine led to the downregulation of mesenchymal cell markers that was accompanied by reduced cell motility. Similar inhibitory effects were also observed for isoprenaline, a non-selective ß-adrenergic receptor (ß-AR) agonist. In addition, inhibition of cell migration upon treatment with isoxsuprine was reverted by a non-selective ß-AR antagonist, propranolol, and the CRISPR/Cas9 system-mediated deletion of the ß2-AR gene, suggesting that the effects exerted by isoxsuprine involved signals mediated by ß2-AR. In addition, in a subcutaneous xenograft model of oral cancer cells, the administration of isoxsuprine effectively suppressed primary tumor growth, suggesting ß2-AR signals to be a promising cancer therapeutic target for treatment of OSCC.
Subject(s)
Carcinoma, Squamous Cell/metabolism , Mesenchymal Stem Cells/metabolism , Mouth Neoplasms/metabolism , Receptors, Adrenergic, beta-2/metabolism , Androgen Receptor Antagonists/pharmacology , Animals , Carcinoma, Squamous Cell/drug therapy , Cell Line, Tumor , Cell Movement/drug effects , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/metabolism , Down-Regulation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Humans , Male , Mesenchymal Stem Cells/drug effects , Mice , Mice, Inbred BALB C , Mice, Nude , Mouth Neoplasms/drug therapy , Phenotype , Propranolol/pharmacology , Signal Transduction/drug effectsABSTRACT
Malignant melanoma is one of the untreatable cancers in which conventional therapeutic strategies, including chemotherapy, are hardly effective. Therefore, identification of novel therapeutic targets involved in melanoma progression is urgently needed for developing effective therapeutic methods. Overexpression of interleukin-13 receptor α2 (IL13Rα2) is observed in several cancer types including glioma and pancreatic cancer. Although IL13Rα2 is implicated in the progression of various types of cancer, its expression and roles in the malignant melanoma have not yet been elucidated. In the present study, we showed that IL13Rα2 was expressed in approximately 7.5% melanoma patients. While IL13Rα2 expression in human melanoma cells decreased their proliferation in vitro, it promoted in vivo tumour growth and angiogenesis in melanoma xenograft mouse model. We also found that the expression of amphiregulin, a member of the epidermal growth factor (EGF) family, was correlated with IL13Rα2 expression in cultured melanoma cells, xenograft tumour tissues and melanoma clinical samples. Furthermore, expression of amphiregulin promoted tumour growth, implicating causal relationship between the expression of IL13Rα2 and amphiregulin. These results suggest that IL13Rα2 enhances tumorigenicity by inducing angiogenesis in malignant melanoma, and serves as a potential therapeutic target of malignant melanoma.
