title: Protease-activated receptor-2 induces migration of pancreatic cancer cells in an extracellular ATP-dependent manner.
abstract: BACKGROUND
  Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor suggested to play an important role in the proliferation and migration of tumor cells of epithelial origin. However, the role of PAR-2 in the setting of pancreatic cancer remains largely unexplored.
  
  
  OBJECTIVE
  To understand the importance of PAR-2 in pancreatic cancer cell migration.
  
  
  RESULTS
  The present study shows that PAR-2 does not affect pancreatic cancer cell proliferation but significantly induces the migration of pancreatic cancer cells in scratch assays. Interestingly, PAR-2 does not affect migration in a trans-well setting. This apparent discrepancy depends on extracellular ATP release in the scratch assays and the addition of exogenous (ATP)-induced PAR-2-dependent migration in trans-well assays, whereas a specific P2Y11 receptor antagonist prevents PAR-2-driven migration in scratch assays. In the scratch assays, inhibitors of Src, Rac, protein kinase C, mitogen-activated protein kinase kinase, p38, and epidermal growth factor (EGF) receptor blocked PAR-2-driven migration, whereas they did not affect fetal calf serum-driven wound closure.
  
  
  CONCLUSIONS
  Taken together, PAR-2 activation drives pancreatic cancer cell migration via an EGF-Src-Rac-p38/mitogen-activated protein kinase kinase/EGF1/2 signaling pathway, which is facilitated by extracellular ATP. Targeting the PAR-2/ATP-driven signaling pathway may therefore limit cell migration, which could inhibit pancreatic cancer metastasis.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Shi
authors.forename: K C S
authors.initials: KC
authors.lastname: Queiroz
authors.forename: J
authors.initials: J
authors.lastname: Stap
authors.forename: D J
authors.initials: DJ
authors.lastname: Richel
authors.forename: C A
authors.initials: CA
authors.lastname: Spek
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D044464:Receptor, PAR-2 / Q000502:physiology*
chemical_list: D044464:Receptor, PAR-2; D000255:Adenosine Triphosphate
keywords: ATP; cell migration; pancreatic cancer; protease-activated receptor-2; signal transduction