Indacaterol Inhibits Tumor Cell Invasiveness and MMP-9 Expression by Suppressing IKK/NF-κB Activation

• Published in: Molecules and cells Vol. 37; no. 8; pp. 585 - 591
• Main Authors: Lee, Su Ui, Ahn, Kyung-Seop, Sung, Min Hee, Park, Ji-Won, Ryu, Hyung Won, Lee, Hyun-Jun, Hong, Sung-Tae, Oh, Sei-Ryang
• Format: Journal Article
• Language: Korean
• Published: 2014
• Subjects: indacaterol; invasion; ADRB2; MMP-9; NF- ${\kappa}B
• ISSN: 1016-8478; 0219-1032

The ${\beta}_2$ adrenergic receptor (ADRB2) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder (COPD). Although a number of ADRB2 agonists have been developed for use in asthma therapy, indacaterol is the only ultra-long-acting inhaled ${\beta}_2$-agonist (LABA) approved by the FDA for relieving the symptoms in COPD patients. The precise molecular mechanism underlying the pharmacological effect of indacaterol, however, remains unclear. Here, we show that ${\beta}$-arrestin-2 mediates the internalization of ADRB2 following indacaterol treatment. Moreover, we demonstrate that indacaterol significantly inhibits tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$)-induced NF-${\kappa}B$ activity by reducing levels of both phosphorylated-IKK and -$I{\kappa}B{\alpha}$, thereby decreasing NF-${\kappa}B$ nuclear translocation and the expression of MMP-9, an NF-${\kappa}B$ target gene. Subsequently, we show that indacaterol significantly inhibits TNF-${\alpha}$/NF-${\kappa}B$-induced cell invasiveness and migration in a human cancer cell line. In conclusion, we propose that indacaterol may inhibit NF-${\kappa}B$ activity in a ${\beta}$-arrestin2-dependent manner, preventing further lung damage and improving lung function in COPD patients.