Norepinephrine stimulates pancreatic cancer cell proliferation, migration and invasion via β-adrenergic receptor-dependent activation of P38/MAPK pathway.
OBJECTIVE
There is growing evidence that chronic stress is associated with cancer pathogenesis and progression, but the mechanisms involved in this association are poorly understood. This study aims to examine the effect of stress hormone norepinephrine (NE) on proliferation, migration and invasion of human pancreatic cancer cells and the molecular pathway involved.


METHODS
PANC-1 cells were examined for the expression of β-Adrenergic receptor (β-AR) subtypes, β1-AR, β2-AR by RT-PCR and western blotting, respectively. The PANC-1 cells proliferation, cell cycle distribution, cell migration and invasion were assessed by CCK-8, flow cytometry, scratch wound healing and transwell Matrigel, respectively.


RESULTS
PANC- 1 cells expressed both β1-AR and β2-AR protein. Exposure of PANC-1 cells to increasing concentrations of NE stimulated cell proliferation in a dose-dependent fashion. In addition, NE increased S-phase population and decreased G1 and G2-phase population of PANC- 1 cells. Furthermore, NE significantly enhanced migration and invasion of PANC-1 cells. More strikingly, we observed that NE elevated P38/MAPK phosphorylation (Phos-p38) level. These stimulatory effects were completely abolished by β-AR antagonist propranolol (PRO) or P38/MAPK inhibitor SB203580.


CONCLUSIONS
NE could stimulate pancreatic cancer cell proliferation, migration and invasion through a β-AR-dependent activation of P38/MAPK pathway involved.
Department of Surgery, Shanghai Jiaotong University, Shanghai, China.
Xin-yu
XY
Huang
Hong-cheng
HC
Wang
Zhou
Z
Yuan
Jian
J
Huang
Qi
Q
Zheng
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009361:Neoplasm Invasiveness; D009638:Norepinephrine / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D048051:p38 Mitogen-Activated Protein Kinases; D009638:Norepinephrine