Uridine triphosphate increases proliferation of human cancerous pancreatic duct epithelial cells by activating P2Y2 receptor

Objectives: The aim of this study was to investigate the effect of uridine triphosphate (UTP) on the proliferation of human cancerous pancreatic duct epithelial cells.

Methods: Proliferation was measured by immunoassay for bromodeoxyuridine incorporation into the pancreatic cell line PANC-1. Effect of UTP was assayed using selective P2 agonist and antagonist, small interfering RNA, intracellular signal inhibitors, and Western blot.

Results: Incubation of PANC-1 cells with UTP or MRS2768, a selective P2Y2 Receptor Agonist, resulted in a dose- and time-dependent increase of proliferation. The messenger RNA transcript and protein of P2Y2 receptor were expressed in PANC-1 cells. P2 receptor antagonist suramin and small interfering RNA against P2Y2 receptor significantly decreased the proliferative effect of UTP and MRS2768. Activation of P2Y2 receptor by UTP transduced to Phospholipase C, inositol 1,4,5-triphosphate (IP3), and protein kinase C. Uridine triphosphate-induced proliferation was mediated by protein kinase D, Src-family tyrosine kinase, Ca/calmodulin-dependent protein kinase II, phosphatidylinositol 3-kinase (PI3K), Akt, and Phospholipase D. Uridine triphosphate increased phosphorylation of Akt through protein kinase C, Src-family tyrosine kinase, Ca/calmodulin-dependent protein kinase II, and PI3K.

Conclusions: Uridine triphosphate increases proliferation of human pancreatic duct epithelial cells by activation of P2Y2 receptor and PI3K/Akt pathway. This could be helpful for discovering the long-term roles of P2Y2 receptor in pancreatic cells.