Abstract
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.
Highlights
Prostate cancer (PCa) is the second most frequently diagnosed cancer and the fifth leading cause of cancer deaths in men [1]
The results show that the RNA (CT value < 35) of P2X4, X5, X7, Y1, Y4, Y13, and Y14 receptors are expressed in all three cell lines (Figure 1A,B)
To further examine whether P2X4 receptor (P2X4R) is functional in PCa cells, we tested the adenosine -triphosphate (ATP)-induced calcium influx changes under the influence of the P2X4R specific antagonists 5-BDBD and PSB-12062
Summary
Prostate cancer (PCa) is the second most frequently diagnosed cancer (more than 1.3 million new cases worldwide in 2018) and the fifth leading cause of cancer deaths (over 350,000 deaths annually) in men [1]. PCa cells [23], indicating a functional role of P2X4R in PCa progression [24]. P2X4R was shown to be involved in TGFβ-1 induced invasiveness and epithelial-to-mesenchymal transition (EMT) in PCa cells [25]. These studies suggested a complex link between P2X4R and PCa activities. P2X4R activity enhances tumour formation by PCa cells. To achieve this objective, we have first examined the transcriptional expression of P2 receptors in several PCa cells lines and determined whether the expressed P2X4R are functional. Using publicly available clinical datasets, the association between P2X4R expression and PCa disease progression was established
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