The Cytolytic P
 2Z
 Receptor for Extracellular ATP Identified as a P
 2X
 Receptor (P2X
 7
 )

Surprenant, Annmarie; Rassendren, François; Kawashima, Eric; North, Richard; Buell, Gary

doi:10.1126/science.272.5262.735

Cited by 1,640 publications

(1,688 citation statements)

References 22 publications

(4 reference statements)

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“…P2X 7 R is an intriguing receptor from which pharmacological activation is generally associated to cytotoxic effects (Surprenant et al, 1996;Di Virgilio et al, 1998) therefore leading to the hypothesis that their overexpression or stimulation could be deleterious for cells. Surprisingly, it was found that P2X 7 R is expressed at very high levels in several tumours, compared with Deli et al, 2007;Solini et al, 2008) and was even proposed to represent an early cancer marker (Slater et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

et al. 2011

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ATP-gated P2X 7 receptors (P2X 7 R) are unusual plasma membrane ion channels that have been extensively studied in immune cells. More recently, P2X 7 R have been described as potential cancer cell biomarkers. However, mechanistic links between P2X 7 R and cancer cell processes are unknown. Here, we show, in the highly aggressive human breast cancer cell line MDA-MB-435s, that P2X 7 receptor is highly expressed and fully functional. Its activation is responsible for the extension of neurite-like cellular prolongations, of the increase in cell migration by 35% and in cell invasion through extracellular matrix by 150%. The change in cancer cell morphology and the increased migration appeared to be due to the activation of Ca 2 þ -activated SK3 potassium channels. The enhanced invasion through the extracellular matrix was related to the increase of mature forms of cysteine cathepsins in the extracellular medium, which was independent of SK3 channel activity and not associated with cell death. Pharmacological targeting of P2X 7 R in vivo was crucial for cell invasiveness in a zebrafish model of metastases. Our results demonstrate a novel mechanistic link between P2X 7 R functionality in cancer cells and invasiveness, a key parameter in tumour growth and in the development of metastases. They also suggest a potential therapeutic role for the newly developed P2X 7 R antagonists.

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Section: Discussionmentioning

confidence: 99%

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

et al. 2011

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“…functioning as a neuromodulator at glutamatergic synapses (Gu and MacDermott, 1997), while millimolar concentrations, released into the extracellular milieu in response to injury, can act, via P2X7, as a DAMP, initiating neuroinflammatory cascades (Fiebich et al, 2014). Secondly, the pore-forming functionality of the P2X7 receptor facilitates the release of larger hydrophilic molecules, up to 900 Da (Surprenant et al, 1996), a process which may be important for initiating neuroinflammation. Indeed, the formation of the P2X7 receptor pore seems to be necessary for the role of the molecule in activating the inflammasome (Monif et al, 2009).…”

Section: The Role Of P2x Receptors In Neuroinflammationmentioning

confidence: 99%

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

et al. 2016

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a b s t r a c tThe principle functions of neuroinflammation are to limit tissue damage and promote tissue repair in response to pathogens or injury. While neuroinflammation has utility, pathophysiological inflammatory responses, to some extent, underlie almost all neuropathology. Understanding the mechanisms that control the three stages of inflammation (initiation, propagation and resolution) is therefore of critical importance for developing treatments for diseases of the central nervous system. The purinergic signaling system, involving adenosine, ATP and other purines, plus a host of P1 and P2 receptor subtypes, controls inflammatory responses in complex ways. Activation of the inflammasome, leading to release of pro-inflammatory cytokines, activation and migration of microglia and altered astroglial function are key regulators of the neuroinflammatory response. Here, we review the role of P1 and P2 receptors in mediating these processes and examine their contribution to disorders of the nervous system. Firstly, we give an overview of the concept of neuroinflammation. We then discuss the contribution of P2X, P2Y and P1 receptors to the underlying processes, including a discussion of cross-talk between these different pathways. Finally, we give an overview of the current understanding of purinergic contributions to neuroinflammation in the context of specific disorders of the central nervous system, with special emphasis on neuropsychiatric disorders, characterized by chronic low grade inflammation or maternal inflammation. An understanding of the important purinergic contribution to neuroinflammation underlying neuropathology is likely to be a necessary step towards the development of effective interventions.

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“…The receptor exists in several splice isoforms (A–J) and single nucleotide polymorphisms (SNPs) correlate with several diseases 11, 12. The P2X7R is a ligand‐gated ion channel permeable to Ca 2+ , K + and Na + 13. Following sustained activation or overstimulation, this receptor forms or facilitates formation of pores permeable to large molecules that can lead to cell lysis and death 14, 15.…”

Section: Introductionmentioning

confidence: 99%

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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The Cytolytic P _2Z Receptor for Extracellular ATP Identified as a P _2X Receptor (P2X ₇ )

Cited by 1,640 publications

References 22 publications

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

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The Cytolytic P 2Z Receptor for Extracellular ATP Identified as a P 2X Receptor (P2X 7 )

Cited by 1,640 publications

References 22 publications

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Contact Info

Product

Resources

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The Cytolytic P _2Z Receptor for Extracellular ATP Identified as a P _2X Receptor (P2X ₇ )