Activation of β2-adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells.

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. Furthermore, recent lines of evidence suggest that EMT confers cancer cells with tumor initiating ability. Thus, selective targeting of EMT would lead to the development of effective therapeutic agents. In this study, using chemical biology approach, we identified isoxsuprine, a β2-adrenergic receptor (β2-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 β-adrenergic receptor (β-AR) agonist. In addition, inhibition of cell migration upon the treatment with isoxsuprine was reverted by a non-selective β-AR antagonist, propranolol, and CRISPR/Cas9 system-mediated deletion of β2-AR gene, suggesting that the effects exerted by isoxsuprine involve the signals mediated by β2-AR. In addition, in subcutaneous xenograft model of oral cancer cells, the administration of isoxsuprine effectively suppressed primary tumor growth suggesting β2-AR signals to be a promising cancer therapeutic target for treatment of OSCC.