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Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells
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Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells
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Journal Article
Activation of β2‐adrenergic receptor signals suppresses mesenchymal phenotypes of oral squamous cell carcinoma cells
2021
Overview
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 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 treatment with isoxsuprine was reverted by a non‐selective β‐AR antagonist, propranolol, and the CRISPR/Cas9 system‐mediated deletion of the β2‐AR gene, suggesting that the effects exerted by isoxsuprine involved signals mediated by β2‐AR. In addition, in a 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. In this study we identified isoxsuprine, a β2‐adrenergic receptor agonist as an effective inhibitor of mesenchymal phenotypes and migration of oral squamous cell carcinoma cells suggesting that β2‐adrenergic receptor signal is a new promising therapeutic target for treatment of oral cancer.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc
Subject
/ Agonists
/ Androgen Receptor Antagonists - pharmacology
/ Animals
/ Carcinoma, Squamous Cell - drug therapy
/ Carcinoma, Squamous Cell - metabolism
/ Cell Movement - drug effects
/ Cell Transformation, Neoplastic - drug effects
/ Cell Transformation, Neoplastic - metabolism
/ Cell, Molecular, and Stem Cell Biology
/ CRISPR
/ Down-Regulation - drug effects
/ Epithelial-Mesenchymal Transition - drug effects
/ Genomes
/ Humans
/ Kinases
/ Male
/ Mesenchymal Stem Cells - drug effects
/ Mesenchymal Stem Cells - metabolism
/ MET (mesenchymal‐epithelial transition)
/ Mice
/ Motility
/ Mouth Neoplasms - drug therapy
/ Mouth Neoplasms - metabolism
/ Oral squamous cell carcinoma
/ Original
/ Plasmids
/ Proteins
/ Receptors, Adrenergic, beta-2 - metabolism
/ Signal Transduction - drug effects
/ Tumors
