Indacaterol inhibits tumor cell invasiveness and MMP-9 expression by suppressing IKK/NF-κB activation

Mol Cells. 2014 Aug;37(8):585-91. doi: 10.14348/molcells.2014.0076. Epub 2014 Aug 18.


The β2 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 β2-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 β-arrestin-2 mediates the internalization of ADRB2 following indacaterol treatment. Moreover, we demonstrate that indacaterol significantly inhibits tumor necrosis factor-α (TNF-α)-induced NF-κB activity by reducing levels of both phosphorylated-IKK and -IκBα, thereby decreasing NF-κB nuclear translocation and the expression of MMP-9, an NF-κB target gene. Subsequently, we show that indacaterol significantly inhibits TNF-α/NF-κB-induced cell invasiveness and migration in a human cancer cell line. In conclusion, we propose that indacaterol may inhibit NF-κB activity in a β-arrestin2-dependent manner, preventing further lung damage and improving lung function in COPD patients.

Keywords: ADRB2; MMP-9; NF-κB; indacaterol; invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Arrestins / genetics
  • Arrestins / metabolism
  • Cell Movement / drug effects
  • Gene Expression Regulation, Neoplastic*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Indans / pharmacology*
  • Luciferases / genetics
  • Luciferases / metabolism
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinase 9 / metabolism
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Protein Interaction Mapping
  • Protein Transport / drug effects
  • Quinolones / pharmacology*
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • beta-Arrestin 2
  • beta-Arrestins


  • ADRB2 protein, human
  • ARRB2 protein, human
  • Adrenergic beta-2 Receptor Agonists
  • Arrestins
  • Indans
  • NF-kappa B
  • Quinolones
  • Receptors, Adrenergic, beta-2
  • Recombinant Fusion Proteins
  • beta-Arrestin 2
  • beta-Arrestins
  • Green Fluorescent Proteins
  • indacaterol
  • Luciferases
  • I-kappa B Kinase
  • Matrix Metalloproteinase 9