P2X7 receptor stimulates breast cancer cell invasion and migration via the AKT pathway

Xia, Jianguo; Yu, Xiaolan; Tang, Li; Li, Gang; He, Tao

doi:10.3892/or.2015.3979

Cited by 101 publications

(94 citation statements)

References 31 publications

(31 reference statements)

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“…Here, we demonstrated that cancer cells migration was increased in vitro by P2X7R stimulation and inhibited by AZ10606120 (Figs 3a-3c). Our data are in line with other studies showing the role of P2X7R in migration in breast cancer cells, 18,39 lung cancer cells 40 and prostate cancer cells. 41 In stroma-rich PDAC interplay between cancer cells and PSCs, which has been termed as the "deadly symbiosis", leads to a massive cancer cell migration and invasion.…”

Section: Discussionsupporting

confidence: 93%

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Giannuzzo

Saccomano

Napp

et al. 2016

Intl Journal of Cancer

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The ATP‐gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu‐1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu‐1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7‐/‐ animals. PancTu‐1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120‐treated mice showed reduced bioluminescence compared to saline‐treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120‐treated tumours.

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Section: Discussionsupporting

confidence: 93%

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Giannuzzo

Saccomano

Napp

et al. 2016

Intl Journal of Cancer

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“…It was demonstrated that P2X7 receptor activation enhances invasiveness through a mechanism involving Ca 2+ -activated SK3 K + -channel activity in the mammary carcinoma cell line MDA-MB-435 s [65]. In addition, P2X7 receptor activation in T47D breast cancer cells induces an increase in cell invasiveness associated with the expression of EMT markers, such as E-cadherin and MMP-13, via the AKT pathway [66].…”

Section: Adora2amentioning

confidence: 99%

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Martinez-Ramirez

Dı́az-Muñoz

Butanda-Ochoa

et al. 2016

Purinergic Signalling

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The epithelium-mesenchymal transition (EMT) is an important process of cell plasticity, consisting in the loss of epithelial identity and the gain of mesenchymal characteristics through the coordinated activity of a highly regulated informational program. Although it was originally described in the embryonic development, an important body of information supports its role in pathology, mainly in cancerous and fibrotic processes. The purinergic system of inter-cellular communication, mainly based in ATP and adenosine acting throughout their specific receptors, has emerged as a potent regulator of the EMT in several pathological entities. In this context, cellular signaling associated to purines is opening the understanding of a new element in the complex regulatory network of this phenotypical differentiation process. In this review, we have summarized recent information about the role of ATP and adenosine in EMT, as a growing field with high therapeutic potential.Keywords P2 receptors . P1 receptors . Purinergic signaling . Cell migration . EMTThe purinergic system of intercellular communication General aspects The term purine (from: pure urine) was created more than 130 years ago by Emil Fischer after detailed analytical characterization of the uric acid molecule [1]. Purine molecular structure is the result of fusing pyrimidine and imidazole rings, and it exists as four N-H tautomeric forms [2]. Tautomerism of purine bases in DNA is one of the earliest reasons for mutations [3][4][5]. The interconversion of the different adenine or guanine tautomers produced mispairing with pyrimidines (which also show tautomeric forms) that may lead to changes in DNA sequence [6].Purine molecules appeared very early in the history of our planet, in the period known as Borganic evolution^, before the establishment of living systems. It has been postulated that purines could be formed by a eutectic (denoting a mixture of substances in fixed proportions that melts and freezes at a single temperature that is lower than the melting points of any of the separate constituents) concentration of HCN at extremely low temperature over a period of dozens of years [7]. Purine molecules, such as adenine and guanine, are components of the genetic material (DNA and RNA) of all living beings. Purine and pyrimidine tautomeric equilibria in nucleic acids was postulated to be significant in events such as DNA replication and repair as well as in the occurrence of point mutations [8].As nucleosides and nucleotides, purines play other highly strategic roles, acting as energy intermediates, allosteric regulators of key metabolic activities, redox molecules, and chemical messengers for signal transduction events. The two most important purines serving as extracellular ligands for paracrine and autocrine signaling are ATP and its dephosphorylated form, adenosine (ADO). ATP and ADO act as intracellular intermediate metabolites, and their presence in the

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“…With its relatively low sensitivity to ATP, P2X7R is a good candidate for a receptor that will function in such a high-ATP environment. Concordantly, several studies have suggested that P2X7R is an important, even a central player in key processes related to inflammation and cancer such as the activation of interleukin 1b (IL-1b) processing most probably via NLRP3 (nucleotidebinding oligomerization domain, leucine rich repeat, and pyrin domain containing 3) inflammasome complex in macrophagelike immune cells (Ferrari et al, 1997a;Solle et al, 2001; for details, see Adinolfi et al, 2018), in vivo growth (Adinolfi et al, 2012;Amoroso et al, 2015), and invasion of cancer cells (Ferrari et al, 2006;Xia et al, 2015;Di Virgilio and Adinolfi, 2017;.…”

Section: Introductionmentioning

confidence: 99%

A Mechanism-Based Approach to P2X7 Receptor Action

Uğur

2019

Mol Pharmacol

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The ligand-gated ion channel P2X7 receptor attracts special attention due to its widespread presence as well as its unusual responses. Besides relatively well-understood mechanisms such as intracellular Ca 21 increase and K 1 depletion, the P2X7 receptor activates other peculiar responses whose mechanisms are not fully understood. The best known among these is the permeabilization of the cell membrane to large molecules. This permeabilization has been explained by the activation of a nonselective permeation pathway by the P2X7 receptor, a phenomenon called "pore formation." However, with the emergence of new data, it became apparent that large molecules enter the cell directly through the pore of the ion channel, similar to the smaller ions. This explanation seems to be true for cationic large molecules. On the other hand, there is still convincing evidence indicating that the P2X7 receptor activates a separate pathway that permeates anionic large molecules in some cell types. Furthermore, there exist functional data suggesting that the P2X7 receptor may also activate other intracellular signaling molecules or other ion channels. Interestingly and contrary to what is expected from a ligand-gated channel, these activations occur in a seemingly direct manner. Somewhat overshadowed by the pore formation hypothesis, these action mechanisms may lead to a better understanding of not only the P2X7 receptor itself but also some important physiologic functions such as the release of anionic autocoids/neurotransmitters in the central nervous system. This review discusses, assesses, and draws attention to the data concerning these neglected but potentially important points in the P2X7 receptor field. ABBREVIATIONS: AKT, protein kinase B; HEK293, human embryonic kidney cells; IL-1b, interleukin 1b; LDH, lactate dehydrogenase enzyme; Ni-AchR, nicotinic acetylcholine receptor; NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain containing 3; NMDG, N-methyl-D-glucamine; PLA2, phospholipase A2 enzyme; PLD, phospholipase D enzyme; P2X2(4,7)R, P2X purinergic receptor 2(4,7); ToTo-1, 1,1ʹ-(4,4,7,7-tetramethyl-4,7-diazaundecamethylene)-bis-4-(3-methyl-2,3-dihydro-(benzo-1,3-thiazole)-2-methylidene)-quinolinium tetraiodide; TRPV, transient receptor potential cation channel V; YoPro-1, 4-((3-methyl-2(3H)-benzoxazolylidene)methyl)-1-(3-(trimethylammonio)propyl) quinolinium diiodide.

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P2X7 receptor stimulates breast cancer cell invasion and migration via the AKT pathway

Cited by 101 publications

References 31 publications

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

A Mechanism-Based Approach to P2X7 Receptor Action

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