Inhibiting the P2X4 Receptor Suppresses Prostate Cancer Growth In Vitro and In Vivo, Suggesting a Potential Clinical Target

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.

Purinergic P2Y2 and P2X4 Receptors Are Involved in the Epithelial-Mesenchymal Transition and Metastatic Potential of Gastric Cancer Derived Cell Lines

“…Conversely, when knockdown strategies were applied for both receptors, an inverse trend of cell proliferation inhibition and stimulation for P2Y2 KD and P2X4 KD, respectively, appeared for the studied cell lines. These effects on cell proliferation are in accordance with those observed in pharmacological assays performed on P2Y2R in gastric cancer [14], pancreatic ductal adenocarcinoma [47], esophageal [48], breast carcinoma [49], and on P2X4R in gastric [14], breast [50], and prostate cancer [51]. Interestingly, in MKN-45 cells P2Y2R KD did not have any effect on cell proliferation; however, this result was not unexpected, since previous reports using 1-300 µM applications with the P2Y2R agonist UTP in this cell line had minor effects on cell proliferation [14]; conversely, P2X4R OE was a successful strategy for reducing cell proliferation on this cell line.…”

Lysosome purinergic receptor P2X4 regulates neoangiogenesis induced by microvesicles from sarcoma patients

“…The present study shows that T-MVs from sarcoma patients can activate neangiogenesis in non-pathological conditions and tumor environments, and that this is reduced by pharmacologic and genetic inhibition of P2XR4. Purinergic signaling has been shown to mediate a variety of cancer-related processes in the tumor microenvironment [ 27 , 28 ]. P2XR4 was previously reported to control vascular tone and remodeling in response to hypoxia [ 29 ] pulmonary hypertension [ 30 ], inflammation and pain in dorsal root neuron ganglions [ 31 ], cell motility in immune response [ 24 ], and mediated thymosin b-4 HUVEC motility [ 32 ].…”

P2X4 Purinergic Receptors as a Therapeutic Target in Aggressive Prostate Cancer

“…While P2 purinergic receptors have been widely investigated in different cancer sites, studies on P2X4 receptor expression and function in cancer have rarely been reported (20,21,24-28). A recent study identified the P2X4 purinergic receptor as a potential clinical target for patients with PCa (29). The authors demonstrate that pharmacological inhibition of P2X4 receptors impaired PCa cell growth and decreased PCa cell motility (29).…”

“…A recent study identified the P2X4 purinergic receptor as a potential clinical target for patients with PCa (29). The authors demonstrate that pharmacological inhibition of P2X4 receptors impaired PCa cell growth and decreased PCa cell motility (29).…”

“…P2 purinergic receptor overexpression is reported in multiple cancer types and correlates with poorer outcomes (24)(25)(26)(27)(28). P2X4 purinergic receptor expression was identified as the most highly expressed P2 purinergic receptor in PC3, LNCaP, and C4-2B PCa cell lines and P2X4 antagonists had anti-tumorigenic effects in a PCa xenograft model (29). However, the cellular localization and function of P2 purinergic receptors and their association with PCa outcomes is not fully described.…”