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

Abstract

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. To understand the importance of PAR-2 in pancreatic cancer cell migration. 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. 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.