Protease‐activated receptor‐2 induces migration of pancreatic cancer cells in an extracellular ATP‐dependent manner

Summary 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. Objectives To understand the importance of PAR‐2 in pancreatic cancer cell migration. Methods and 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. Conclusion 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.