The Mellanby Centre for Bone Research, Department of Oncology and Metabolism, The University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Cells. 2020 Nov 20;9(11):2511. doi: 10.3390/cells9112511.
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 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.
前列腺癌（PCa）是男性最常见的癌症，导致相当高的发病率和死亡率。P2X4 受体（P2X4R）是哺乳动物中表达最广泛的 P2X 受体，与许多癌症类型的肿瘤发生呈正相关。然而，其在 PCa 进展中的作用尚不清楚。我们假设 P2X4R 活性增强了 PCa 细胞的肿瘤形成。我们使用定量逆转录 PCR（RT-PCR）和钙内流测定法表明，P2X4R 是这些细胞中表达最丰富、功能最强的 P2 受体。使用选择性 P2XR4 拮抗剂 5-BDBD 和 PSB-12062 研究了抑制 P2X4R 对 PCa（PC3 和 C4-2B4 细胞）活力、增殖、迁移、侵袭和凋亡的影响。结果表明，抑制 P2X4R 会损害 PCa 细胞的生长和迁移能力，但不会引起细胞凋亡。在皮下接种人 PC3 细胞的 BALB/c 免疫功能低下裸鼠中，5-BDBD 显示出抗肿瘤作用。最后，对临床数据集（GDS1439、GDS1746 和 GDS3289）中表达的回顾性分析表明，P2X4R 与 PCa 的恶性程度呈正相关。这些研究表明，P2X4R 在增强 PCa 肿瘤形成中起作用，是一个有临床靶向性的候选靶点，已有抑制剂可用，并有可能抑制疾病进展。
