ERK1/2 and p38 pathways are required for P2Y receptor-mediated prostate cancer invasion.

The G protein-coupled P2Y purinoceptors have wide physiological functions, but their role(s) in tumor progression remain unclear. Here, we report that stimulation of P2Y receptors enhances prostate cancer cell invasion in two human prostate carcinoma cell lines, which is mediated by ERK1/2 and p38 signaling pathways. P2Y agonists stimulated prostate cancer cell invasion, and increased the activities of ERK1/2 and p38 protein kinases. The stimulated cancer cell invasion was inhibited by the presence of MEK1 inhibitor PD98059 or p38 inhibitor SB203580. Expression of dominant-negative mutant of MEK1 (KA-MEK1), or up-regulation of MKP-5 (a dual-specificity phosphatase of p38), both reduced the invasion of cultured prostate cancer cells. These results suggest that P2Y receptors and their down-stream ERK1/2 and p38 protein kinases are important regulators promoting prostate cancer invasion.