Prostate cancer (PCa) is the most frequently diagnosed cancer in men, causing considerable morbidity and mortality. The P2X4 receptor (P2X4R) is the most ubiquitously expressed P2X receptor in mammals and is positively associated with tumorigenesis in many cancer types. However, its involvement in PCa progression is less understood. We hypothesized that P2X4R activity enhanced tumour formation by PCa cells. We showed that P2X4R was the most highly expressed, functional P2 receptor in these cells using quantitative reverse transcription PCR (RT-PCR) and a calcium influx assay. The effect of inhibiting P2X4R on PCa (PC3 and C4-2B4 cells) viability, proliferation, migration, invasion, and apoptosis were examined using the selective P2XR4 antagonists 5-BDBD and PSB-12062. The results demonstrated that inhibiting P2X4R impaired the growth and mobility of PCa cells but not apoptosis. In BALB/c immunocompromised nude mice inoculated with human PC3 cells subcutaneously, 5-BDBD showed anti-tumourigenic effects. Finally, a retrospective analysis of P2RX4 expression in clinical datasets (GDS1439, GDS1746, and GDS3289) suggested that P2X4R was positively associated with PCa malignancy. These studies suggest that P2X4R has a role in enhancing PCa tumour formation and is a clinically targetable candidate for which inhibitors are already available and have the potential to suppress disease progression.
Dear EditorBone is the most common site for metastasis in prostate cancer (PCa), and identifying clinically useful biomarkers to predict the risk of currently incurable bone metastases is a major priority in PCa research.Extracellular adenosine triphosphate (ATP) was shown to be a major biochemical constituent of the tumor microenvironment and regulates the tumor and host interactions by acting at P2 purinergic receptors. Among the P2 receptors, the ion channel P2X purinergic receptor 7 (P2X7R) has an unusually long C-terminus containing 200 amino acids, which forms the molecular basis for the unique bi-function of P2X7R promoting cancer cell proliferation or inducing membrane permeabilization and apoptosis, upon activation by a low or high concentration of ATP, respectively. A cysteine-rich region and a guanosine diphosphate or triphosphate (GDP/GTP)-binding site located in the C-terminus are pivotal for the structural rearrangement of the second transmembrane domain helix and the globular ballast underneath during the membrane pore permeabilization [1].Among the 10 human P2X7R splice variants (P2X7RA-J), the P2X7RA variant is the full-length "wild-type (WT)" receptor, while the truncated P2X7RB variant lacks the intracellular C-terminal tail. This naturally occurring P2X7RB isoform maintains ATP-stimulated channel activity but not pore permeabilization [2, 3]. P2X7RB is upregulated in epithelial cancer cells [3] and associated with the trophic activity of primary bone cancer [2,4,5]. These findings have highlighted the importance of defining the role of P2X7R C-terminal truncated variants in cancer progression, particularly considering that data on
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