title: Norepinephrine inhibits the migratory activity of pancreatic cancer cells.
abstract: We have shown previously that norepinephrine induces migratory activity of tumour cells from breast, colon and prostate tissue via activation of beta-2 adrenergic receptors. Consequently, this effect can be inhibited pharmacologically by clinically established beta-blockers. Tumour cell migration is a prerequisite for metastasis formation, and accordingly we and others have shown that breast cancer patients, which take beta-blockers due to hypertension, have reduced metastasis formation and increased survival probability as compared to patients without hypertension or using other anti-hypertensive medication. Unlike the aforementioned tumour cells, pancreatic cancer cells show a reduced migratory activity upon norepinephrine treatment. By means of our three-dimensional, collagen-based cell migration assay, we have investigated the signal transduction pathways involved in this phenomenon. We have found that this conflicting effect of norepinephrine on pancreatic cancer cells is due to an imbalanced activation of the two pathways that usually mediate a pro-migratory effect of norepinephrine in other tumour cell types. Firstly, the inhibitory effect results from activation of a pathway which causes a strong increase of the secondary cell signalling molecule, cAMP. In addition, activation of phospholipase C gamma and the downstream protein kinase C alpha were shown to be already activated in pancreatic cancer cells and cannot be further activated by norepinephrine. We hypothesize that this constitutive activation of the phospholipase C gamma pathway is due to a cross-talk with receptor tyrosine kinase signalling, and this might also deliver an explanation for the unusual high spontaneous migratory activity of pancreatic cancer cells.
authors: Institute of Immunology and Experimental Oncology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany.
authors: Anna-Maria
authors: AM
authors: Stock
authors: Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, UK.
authors: Desmond G
authors: DG
authors: Powe
authors: Department of Molecular Gastroenterological Oncology, Centre of Clinical Research, Ruhr-University of Bochum, 44780 Bochum, Germany.
authors: Stephan A
authors: SA
authors: Hahn
authors: Institute of Immunology and Experimental Oncology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany.
authors: Gabriele
authors: G
authors: Troost
authors: Institute of Immunology and Experimental Oncology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany.
authors: Bernd
authors: B
authors: Niggemann
authors: Institute of Immunology and Experimental Oncology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany.
authors: Kurt S
authors: KS
authors: Zänker
authors: Institute of Immunology and Experimental Oncology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany. Electronic address: entschladen@uni-wh.de.
authors: Frank
authors: F
authors: Entschladen
mesh_terms: D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D009638:Norepinephrine / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000242:Cyclic AMP; D051571:Protein Kinase C-alpha; D051966:Phospholipase C gamma; D009638:Norepinephrine