The P2 purinoceptors in prostate cancer

Abstract

P2 purinoceptors are composed of ligand-gated ion channel type (P2X receptor) and G protein-coupled metabolite type (P2Y receptor). Both these receptors have played important roles in the prostate cancer microenvironment in recent years. P2X and P2Y receptors can contribute to prostate cancer's growth and invasiveness. However, the comprehensive mechanisms have yet to be identified. By summarizing the relevant studies, we believe that P2X and P2Y receptors play a dual role in cancer cell growth depending on the prostate cancer microenvironment and different downstream signalling pathways. We also summarized how different signalling pathways contribute to tumor invasiveness and metastasis through P2X and P2Y receptors, focusing on understanding the specific mechanisms led by P2X4, P2X7, and P2Y2. Statins may reduce and prevent tumor progression through P2X7 so that P2X purinergic receptors may have clinical implications in the management of prostate cancer. Furthermore, P2X7 receptors can aid in the early detection of prostate cancer. We hope that this review will provide new insights for future mechanistic and clinical investigations into the role of P2 purinergic receptors in prostate cancer.

Keywords: Akt; ERK1/2; P2 purinoceptors; P2XR; P2YR; Prostate cancer.

Fig. 1

The pathway of P2XR in prostate cancer. When initiating the feedforward cycle of ATP release and P2X4 and P2X7, it increases intracellular Ca²⁺ and triggers the involvement of MAPKs, p38, ERK1/2, and PI3K. Meanwhile, the PI3K-AKT-mTOR pathway and multiple interacting cellular signaling cascades, especially the complex crosstalk between MAPK and AR, can further promote growth and metastasis in prostate cancer cells. In contrast to growth, ATP can inhibit CRPC cell growth by 90% through a rapid, transient increase in cytoplasmic free Ca²⁺ by P2X5, inducing apoptosis in a Ca.²⁺-independent mechanism

Fig. 2

The pathway of P2YR in prostate cancer. The activation of P2Y2, in turn, activated Src, which phosphorylated p38 leading to COX-2 overexpression, causing resistance to apoptosis in prostate cancer cells. By contrast, P2Y1 and P2Y11 receptors induce phosphorylation of ERK1/2, and activation of P2Y1R induced apoptosis via the caspase 3/7 and reactive oxygen species (ROS) signaling pathway