Potential role of P2X7R in esophageal squamous cell carcinoma proliferation

Abstract

Esophageal cancer is an aggressive tumor and is the sixth leading cause of cancer death worldwide. ATP is well known to regulate cancer progression in a variety of models by different mechanisms, including P2X7R activation. This study aimed to evaluate the role of P2X7R in esophageal squamous cell carcinoma (ESCC) proliferation. Our results show that treatment with high ATP concentrations induced a decrease in cell number, cell viability, number of polyclonal colonies, and reduced migration of ESCC. The treatment with the selective P2X7R antagonist A740003 or siRNA for P2X7 reverted this effect in the KYSE450 cell line. In addition, results showed that P2X7R is highly expressed, at mRNA and protein levels, in KYSE450 lineage. Additionally, KYSE450, KYSE30, and OE21 cells express P2X3R, P2X4R, P2X5R, P2X6R, and P2X7R genes. P2X1R is expressed by KYSE30 and KYSE450, and only KYSE450 expresses the P2X2R gene. Furthermore, esophageal cancer cell line KYSE450 presented higher expression of E-NTPDases 1 and 2 and of Ecto-5′-NT/CD73 when compared to normal cells. This cell line also exhibits ATPase, ADPase, and AMPase activity, although in different levels, and the co-treatment of apyrase was able to revert the antiproliferative effects of ATP. Moreover, results showed high immunostaining for P2X7R in biopsies of patients with esophageal carcinoma, indicating the involvement of this receptor in the growth of this type of cancer. The results suggest that P2X7R may be a potential pharmacological target to treat ESCC and can lead us to further investigate the effect of this receptor in cancer cell progression.Electronic supplementary material The online version of this article

Multifaceted Effects of Extracellular Adenosine Triphosphate and Adenosine in the Tumor–Host Interaction and Therapeutic Perspectives

“…P2X7 receptor activation also triggers NFATc1, Erk, PI3K/Akt, and HIF-1α intracellular pathways ( 101 – 103 ), being the PI3K/Akt pathway linked to the P2X7-dependent tumor cell growth, invasiveness, metastatic spreading, and angiogenesis ( 101 , 104 ). Also supporting a role for P2X7 receptor in tumor growth is the fact that many types of cancer such as leukemia ( 98 , 105 , 106 ), melanoma ( 107 ), neuroblastoma ( 108 ), pancreatic adenocarcinoma ( 109 ), esophageal carcinoma ( 110 ), breast ( 111 ), prostate ( 112 ), thyroid ( 113 ), and head and neck cancer ( 114 ) showed an increased expression of P2X7 receptor. Moreover, in vivo experiments demonstrated that blocking P2X7 receptor activation by either silencing or a pharmacological manipulation decreased tumor progression and inhibited metastatic diffusion ( 100 , 115 ).…”

The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

“…P2X7 inhibition, either by silencing or pharmacological blockade, restrained tumor progression, and metastasis while P2X7 overexpression accelerated it (Jelassi et al, 2011 ; Adinolfi et al, 2012 ). Moreover, high expression levels of P2X7 receptor have been found in many malignant human tumors, including leukemia (Adinolfi et al, 2002 ; Zhang et al, 2004 ; Chong et al, 2010 ), melanoma (Deli et al, 2007 ), neuroblastoma (Raffaghello et al, 2006 ), pancreatic adenocarcinoma (Giannuzzo et al, 2015 ), esophageal carcinoma (Santos et al, 2017 ), papillary thyroid carcinoma (Kwon et al, 2014 ), renal cell carcinoma (Liu et al, 2015 ), breast cancer (Tan et al, 2015 ), prostate cancer (Ghalali et al, 2014 ), colorectal cancer (Qian et al, 2017 ), and head and neck cancer (Bae et al, 2017 ).…”

Alternative splicing of P2RX7 pre-messenger RNA in health and diseases: Myth or reality?

“…In these cells, P2RX7 expression is involved in chemotaxis, cytokine release, ATP-induced cell death and immunomodulation. In addition, P2RX7 expression was found in both solid [28], [29], [30], [31], [32] and liquid cancers [33], [34], [35], where it was described to sustain cell proliferation or cell death. Other publications claimed that P2RX7 was overexpressed in cancer from various origins [35], [36].…”