title: β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway.
abstract: 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 β2-adrenergic antagonist, we hypothesize that blockage of the β2-adrenoceptor could induce G1/S phase arrest and apoptosis and Ras may be a key player in PanCa cells.
  
  
  RESULTS
  The β1 and β2-adrenoceptor proteins were detected on the cell surface of PanCa cells from pancreatic carcinoma specimen samples by immunohistochemistry. The β2-adrenergic antagonist ICI118,551 significantly induced G1/S phase arrest and apoptosis compared with the β1-adrenergic antagonist metoprolol, which was determined by the flow cytometry assay. β2-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 β2-adrenergic antagonist reduced the activation of NFκB in vitro cultured PanCa cells.
  
  
  CONCLUSIONS
  The blockage of β2-adrenoceptor markedly induced PanCa cells to arrest at G1/S phase and consequently resulted in cell death, which is possibly due to that the blockage of β2-adrenoceptor inhibited NFκB, extracellular signal-regulated kinase, and Akt pathways. Therefore, their upstream molecule Ras may be a key factor in the β2-adrenoceptor antagonist induced G1/S phase arrest and apoptosis in PanCa cells. The new pathway discovered in this study may provide an effective therapeutic strategy for PanCa.
authors: Department of Hepatobiliary and Pancreas Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Dong
authors: D
authors: Zhang
authors: Qingyong
authors: Q
authors: Ma
authors: Zheng
authors: Z
authors: Wang
authors: Min
authors: M
authors: Zhang
authors: Kun
authors: K
authors: Guo
authors: Fengfei
authors: F
authors: Wang
authors: Erxi
authors: E
authors: Wu
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016193:G1 Phase; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D016328:NF-kappa B; D011943:Receptors, Adrenergic, beta; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins