Important roles of P2Y receptors in the inflammation and cancer of digestive system

Wan, Hanxing; Hu, Jianhong; Xie, Rei; Yang, Shi‐Ming; Dong, Hui

doi:10.18632/oncotarget.7518

Cited by 26 publications

(29 citation statements)

References 93 publications

(83 reference statements)

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“…P2 receptors have been studied in further detail and classified as ionotropic P2X receptors (P2XRs) that are nucleotide-gated ion channels and G protein-coupled metabotropic P2Y receptors (P2YRs; Refs. 129,254,487,667). Some P2XRs are associated with cell death, whereas this is not the case for P2YRs (254).…”

Section: Class Ib Dampsmentioning

confidence: 99%

Origin and Consequences of Necroinflammation

Sarhan

Land

Tonnus

et al. 2018

Physiological Reviews

153

152

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When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immunogenic intracellular molecules and organelles into the interstitium and thereby represent the strongest known trigger of the immune system. With our increasing understanding of necrosis as a regulated and genetically determined process (RN, regulated necrosis), necrosis and necroinflammation can be pharmacologically prevented. This review discusses our current knowledge about signaling pathways of necrotic cell death as the origin of necroinflammation. Multiple pathways of RN such as necroptosis, ferroptosis, and pyroptosis have been evolutionary conserved most likely because of their differences in immunogenicity. As the consequence of necrosis, however, all necrotic cells release damage associated molecular patterns (DAMPs) that have been extensively investigated over the last two decades. Analysis of necroinflammation allows characterizing specific signatures for each particular pathway of cell death. While all RN-pathways share the release of DAMPs in general, most of them actively regulate the immune system by the additional expression and/or maturation of either pro- or anti-inflammatory cytokines/chemokines. In addition, DAMPs have been demonstrated to modulate the process of regeneration. For the purpose of better understanding of necroinflammation, we introduce a novel classification of DAMPs in this review to help detect the relative contribution of each RN-pathway to certain physiological and pathophysiological conditions.

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Section: Class Ib Dampsmentioning

confidence: 99%

Origin and Consequences of Necroinflammation

Sarhan

Land

Tonnus

et al. 2018

Physiological Reviews

153

152

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“…Apoptosis is induced by extracellular ATP and ATP also reduced growth of primary cultures of colorectal carcinomas, possibly via P2Y 2 R (see Burnstock and Di Virgilio, 2013 ; Wan H.X. et al, 2016 ).…”

Section: Gut Disordersmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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“…Over the past decades, many studies have highlighted fundamental roles of P2Y receptors in inflammatory diseases. P2Y receptors have been implicated in the release of proinflammatory cytokines by the response to infections, injury, and immunologic challenges in many different cell types . For example, nucleotides induced inflammatory mediators release via P2Y2 and P2Y11 receptors in some cell lines, on the other hand, P2Y receptors seem to have an important immunomodulatory role in a variety of cells.…”

Section: Discussionmentioning

confidence: 99%

Adenosine diphosphate–sensitive P2Y11 receptor inhibits endothelial cell proliferation by induction of cell cycle arrest in the S phase and induces the expression of inflammatory mediators

Chen

Xiao

Yang

et al. 2018

J of Cellular Biochemistry

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Extracellular adenosine diphosphate (ADP) mediates a wide range of physiological effects as an extracellular signaling molecule, including platelet aggregation, vascular tone, cell proliferation, and apoptosis by interacting with plasma membrane P2 receptors. However, the effect of ADP on cell proliferation was contradictory. In this study, we found that ADP significantly inhibited cell proliferation of human umbilical vein endothelial cells at high concentrations (50 to 100 µM). Treatment with ADP did not induce cell apoptosis but instead induced cell cycle arrest in the S phase, which may be partly due to the downregulation of cyclin B1. The inhibition of cell proliferation was blocked by suramin, a nonspecific antagonist of the P2 receptors, and high concentrations of ADP significantly upregulated the messenger RNA (mRNA) and protein expression of P2Y11 in endothelial cells. Moreover, the downregulation of P2Y11 by RNA interference reversed the inhibition of cell proliferation. In addition, ADP (100 µM) can induce the formation of cytosolic autophagy in endothelial cells and a rapid phosphorylation of extracellular signal regulated kinase (ERK) 1/2, which is a canonical signal molecule downstream of P2Y receptors, accompanied by a mRNA expression of proinflammatory cytokines such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Taken together, our study excludes a mechanism for extracellular ADP impairing endothelial cells proliferation via P2Y11 receptor by downregulating cyclin B1 and arresting cell cycle at the S phase, besides, ADP induces cell autophagy and mRNA expression of inflammatory cytokines, whether it is mediated by Erk signaling pathways needs further studies to confirm.

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Important roles of P2Y receptors in the inflammation and cancer of digestive system

Cited by 26 publications

References 93 publications

Origin and Consequences of Necroinflammation

Origin and Consequences of Necroinflammation

Purinergic Signalling: Therapeutic Developments

Adenosine diphosphate–sensitive P2Y11 receptor inhibits endothelial cell proliferation by induction of cell cycle arrest in the S phase and induces the expression of inflammatory mediators

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