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

Abstract

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. he 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.