β ₂-adrenoceptor blockage induces G ₁/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway

Background: 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.