β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway

Smoking and stress, pancreatic cancer (PanCa) risk factors, stimulate nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and catecholamines production respectively. NNK and catecholamine bind the β-adrenoceptors and induce PanCa cell proliferation; and we have previously suggested that β-adrenergic antagonists may suppress proliferation and invasion and stimulate apoptosis in PanCa. To clarify the mechanism of apoptosis induced by β 2 -adrenergic antagonist, we hypothesize that blockage of the β 2 -adrenoceptor could induce G 1 /S phase arrest and apoptosis and Ras may be a key player in PanCa cells. Results The β 1 and β 2 -adrenoceptor proteins were detected on the cell surface of PanCa cells from pancreatic carcinoma specimen samples by immunohistochemistry. The β 2 -adrenergic antagonist ICI118,551 significantly induced G 1 /S phase arrest and apoptosis compared with the β 1 -adrenergic antagonist metoprolol, which was determined by the flow cytometry assay. β 2 -adrenergic antagonist therapy significantly suppressed the expression of extracellular signal-regulated kinase, Akt, Bcl-2, cyclin D1, and cyclin E and induced the activation of caspase-3, caspase-9 and Bax by Western blotting. Additionally, the β 2 -adrenergic antagonist reduced the activation of NFκB in vitro cultured PanCa cells. Conclusions The blockage of β 2 -adrenoceptor markedly induced PanCa cells to arrest at G 1 /S phase and consequently resulted in cell death, which is possibly due to that the blockage of β 2 -adrenoceptor inhibited NFκB, extracellular signal-regulated kinase, and Akt pathways. Therefore, their upstream molecule Ras may be a key factor in the β 2 -adrenoceptor antagonist induced G 1 /S phase arrest and apoptosis in PanCa cells. The new pathway discovered in this study may provide an effective therapeutic strategy for PanCa.