P2Y2 receptor promotes cell invasion and metastasis in prostate cancer cells.

Prostate cancer is the most common cancer in men in Western countries and a leading lethal tumour with increasing incidence worldwide (Papatsoris and Papavassiliou, 2001). Tumour invasion and metastasis remains the most lethal aspect of prostate cancer (Jaeger et al, 2001). Interactions between tumour cells and host organ microenvironments are required for tumour invasion and metastasis. Most of these interactions are now known to be receptor and ligand interactions (Cunha et al, 2003). Extracellular adenosine 5′-triphosphate (ATP) interacts with purinergic receptors and mediates various biological functions in tumours, including cell proliferation, differentiation and death (Abbracchio and Burnstock, 1998). ATP acts via P2 receptors that are further divided into a P2Y family of G-protein-coupled receptors (P2Y1, 2, 4, 6, 11, 12, 13 and 14) and a P2X family of ligand-gated ion channel receptors (P2X1–7) (Von Kugelgen and Harden, 2011). Unlike P2X receptors, for which ATP is the unique ligand, a wide range of purine and pyrimidine nucleotides act as the ligands of P2Y receptors. For P2Y1, P2Y12 and P2Y13 receptors, the preferred ligand is ADP; for P2Y4, uridine 5′-triphosphate (UTP); for P2Y6, UDP; for P2Y11, ATP; and for P2Y14 are sugar nucleotides such as UDP-glucose and UDP-galactose; only for P2Y2 receptor, UTP and ATP are equally active (Di Virgilio, 2012). Our previous study found that ATP could enhance in vitro invasion of human prostate cancer cells via P2Y receptors (Chen et al, 2004). However, the purinergic receptor subtype(s) involved in this process remains elusive. Different P2Y receptor subtypes have been identified in a variety of cancer types, in both primary samples of human cancer tissue and cell lines (Stagg and Smyth, 2010). As one of G-protein-coupled receptors, P2Y2 receptor can transactivate EGFR and increase mitogen-activated protein kinase and phosphoinositide 3-kinase activity in many cancer cells (Soltoff, 1998; Muscella et al, 2003). P2Y2 receptor exerts contrasting effects on cell proliferation of different cancers. It is reported that activation of P2Y2 receptor can lead to an increase in cell growth in most types of cancer such as melanoma and lung tumours (Schafer et al, 2003; White et al, 2005). But in some other cancer types such as oesophageal cancer and colorectal cancer, activation of P2Y2 receptor causes a decrease in cell proliferation (Hopfner et al, 2001; Maaser et al, 2002). Some studies have demonstrated that P2Y2 receptor is overexpressed in colon cancer and pancreatic cancer (Kunzli et al, 2007; Nylund et al, 2007). However, the role of P2Y2 receptor in tumour progression is still poorly understood. Therefore, in this study, we aimed to characterise the function of P2Y2 receptor in the regulation of prostate cancer cell invasion and metastasis and tried to uncover the underlying mechanisms.