The functional role of P2 purinergic receptors in the progression of gastric cancer

Abstract

Studies have confirmed that P2 purinergic receptors (P2X receptors and P2Y receptors) expressed in gastric cancer (GC) cells and GC tissues and correlates with their function. Endogenous nucleotides including ATP, ADP, UTP, and UDP, as P2 purinergic receptors activators, participate in P2 purinergic signal transduction pathway. These activated P2 purinergic receptors regulate the progression of GC mainly by mediating ion channels and intracellular signal cascades. It is worth noting that there is a difference in the expression of P2 purinergic receptors in GC, which may play different roles in the progression of GC as a tumor promoting factor or a tumor suppressor factor. Among them, P2 × 7, P2Y2 and P2Y6 receptors have certain clinical significance in patients with GC and may be used as biological molecular markers for the prediction of patients with GC. Therefore, in this paper, we discuss the functional role of nucleotide / P2 purinergic receptors signal axis in regulating the progression of GC and that these P2 purinergic receptors may be used as potential molecular targets for the prevention and treatment of GC.

Keywords: GC; P2X receptors; P2Y receptors; Treatment.

Fig. 1

P2X receptors activation regulates the growth and metastasis of GC. Extracellular ATP can be secreted by tumor cells and non-tumor cells in microenvironment as an activator of P2X receptors. Activation of P2X receptors (P2 × 7 receptor) activate intracellular signal cascades and regulate the progression of GC including growth, metastasis and EMT by mediating the opening of ion channels (calcium and sodium influx, potassium efflux). P2 × 7 receptor activation promotes the growth of GC cells by mediating calcium signal. Moreover, P2 × 7 receptor activation can promote the growth, metastasis and EMT of GC by activating different intracellular signal transduction (FAK/AKT and ERK1/2). In addition, the activation of P2 × 4 receptor by ATP can also regulate the expression of EMT/ metastasis-related genes and promote the metastasis and EMT formation of GC

Fig. 2

P2Y receptors activation mediates the progression of GC. ATP rich in tumor microenvironment can be further cleaved into nucleotide metabolites by the action of CD39 and CD73. These nucleotides can be used as activators of P2Y receptors. P2Y2 receptor activators (ATP, UTP and MRS2768) activate P2Y2 receptor by coupling Gaq, mobilizing calcium and intracellular signaling pathways (AKT), and further activating downstream signal molecules (GSK-3β), which promote the expression of VEGF and EMT related genes (such as Vimentin and Snail) in GC cells, and promote the growth and metastasis of GC. However, P2Y6 receptor produces complex regulatory mechanisms. UTP or UDP activate P2Y6 receptor to couple Gaq, inhibit the phosphorylation of pRb (PpRb) by mobilizing calcium currents, and prevent the G1/S phase of GC cells. Overexpression of β-catenin can save UTP and inhibit PpRb in GC cells, thus inhibiting the progression of GC