β2-adrenergic receptor activation promotes the proliferation of A549 lung cancer cells via the ERK1/2/CREB pathway

Abstract

Lung cancer is one of the most common cancers worldwide and accounts for 28% of all cancer-related deaths. The expression of the β2-adrenergic receptor (β2-AR), one of the stress-inducible receptors, has been reported to be closely correlated with malignant tumors. However, the role of β2-AR activation in human lung epithelial-derived cancer A549 cells and the underlying mechanisms are not fully understood. In the present study, we found that activation of β2-AR but not β1-AR promoted the proliferation of A549 cells. Isoproterenol (ISO) stimulation of β2-AR induced extracellular signal-regulated kinase 1/2 (ERK1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Blocking the ERK1/2 pathway by U0126 inhibited CREB phosphorylation and also suppressed A549 cell proliferation. Moreover, ISO treatment enhanced the expression of matrix metalloproteinase (MMP) family proteins such as MMP-2, MMP-9, and also vascular endothelial growth factor (VEGF), which were able to be blocked by knockdown of CREB. In conclusion, our data revealed that β2-AR induced ERK1/2 phosphorylation which in turn activated CREB to promote A549 cell proliferation. These findings elucidate potential therapeutic targets for lung cancer treatment.