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Purinergic Signalling in Cancer and Inflammation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2018) | Viewed by 84626

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Special Issue Editor

Dr. Karen Dwyer

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Guest Editor

1. School of Medicine, Faculty of Health, Deakin University, Geelong, VIC 3220, Australia
2. Royal Melbourne Hospital, Parkville, VIC 3050, Australia
Interests: kidney disease; transplantation; metabolic syndrome; insulin resistance; models of care
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Adenosine triphosphate (ATP) is the energy currency of cells. It is also a potent inflammatory molecule, which is released from cells via connexion and pannexin hemi-channels or directly from necrotic cells into the extracellular space. ATP may signal via P2 receptors and this pathway is implicated in a number of pathological states. ATP is rapidly cleared from the extracellular space by ectonucleotidases generating adenosine. Adenosine signals via the P1 receptors and mediates a number of pathophysiological processes. This Special Issue explores the role of purinergic signalling in inflammatory states and cancer.

Prof. Dr. Karen Dwyer
Guest Editor

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Keywords

Purinergic signaling
ATP, adenosine
P2 receptors
P1 receptors, adenosine receptors
Cancer
Inflammation
Ischemia reperfusion injury
Diabetes

Published Papers (12 papers)

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Research

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11 pages, 1716 KiB

Open AccessArticle

Characterization of UDP-Activated Purinergic Receptor P2Y₆ Involved in Japanese Flounder Paralichthys olivaceus Innate Immunity

by Shuo Li, Jiafang Li, Nan Wang, Gaixiang Hao and Jinsheng Sun

Int. J. Mol. Sci. 2018, 19(7), 2095; https://doi.org/10.3390/ijms19072095 - 19 Jul 2018

Cited by 12 | Viewed by 3195

Abstract

Uridine 5’-diphosphate (UDP)-activated purinergic receptor P2Y₆ is a member of a G-protein-coupled purinergic receptor family that plays an important role in mammalian innate immunity. However, the role of the P2Y₆ receptor (P2Y₆R) in fish immunity has not been investigated. In this report, we characterized a P2Y₆R gene from Japanese flounder (Paralichthys olivaceus) and examined its role in fish innate immunity. Sequence analysis reveals that the Japanese flounder P2Y₆R protein is conserved and possesses four potential glycosylation sites. Quantitative real-time RT-PCR analysis shows that P2Y₆R is broadly distributed in all examined Japanese flounder tissues with dominant expression in the liver. In addition, P2Y₆R gene expression was up-regulated in head kidney macrophages (HKMs) upon lipopolysaccharides (LPS) and poly(I:C) stimulations but down-regulated by LPS challenge in peripheral blood leukocytes (PBLs). Furthermore, pharmacological inhibition of the endogenous P2Y₆ receptor activity by the potently selective P2Y₆R antagonist, MRS 2578, greatly up-regulated pro-inflammatory cytokine interleukin (IL)-1β, IL-6 and TNF-α gene expression in PBL cells treated with UDP. Moreover, LPS- and poly(I:C)-induced gene expression of IL-1β and TNF-α in Japanese flounder PBL cells was attenuated significantly by inhibition of P2Y₆R activity with antagonist MRS 2578. Collectively, we, for the first time, showed the involvement of functional purinergic P2Y₆R in fish innate immunity. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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21 pages, 27990 KiB

Open AccessArticle

β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells

by Sebastian Daniel Hiller, Sarah Heldmann, Katrin Richter, Innokentij Jurastow, Mira Küllmar, Andreas Hecker, Sigrid Wilker, Gabriele Fuchs-Moll, Ivan Manzini, Günther Schmalzing, Wolfgang Kummer, Winfried Padberg, J. Michael McIntosh, Jelena Damm, Anna Zakrzewicz and Veronika Grau

Int. J. Mol. Sci. 2018, 19(4), 1126; https://doi.org/10.3390/ijms19041126 - 10 Apr 2018

Cited by 12 | Viewed by 6114

Abstract

While interleukin-1β (IL-1β) is a potent pro-inflammatory cytokine essential for host defense, high systemic levels cause life-threatening inflammatory syndromes. ATP, a stimulus of IL-1β maturation, is released from damaged cells along with β-nicotinamide adenine dinucleotide (β-NAD). Here, we tested the hypothesis that β-NAD controls ATP-signaling and, hence, IL-1β release. Lipopolysaccharide-primed monocytic U937 cells and primary human mononuclear leukocytes were stimulated with 2′(3′)-O-(4-benzoyl-benzoyl)ATP trieethylammonium salt (BzATP), a P2X7 receptor agonist, in the presence or absence of β-NAD. IL-1β was measured in cell culture supernatants. The roles of P2Y receptors, nicotinic acetylcholine receptors (nAChRs), and Ca²⁺-independent phospholipase A2 (iPLA2β, PLA2G6) were investigated using specific inhibitors and gene-silencing. Exogenous β-NAD signaled via P2Y receptors and dose-dependently (IC₅₀ = 15 µM) suppressed the BzATP-induced IL-1β release. Signaling involved iPLA2β, release of a soluble mediator, and nAChR subunit α9. Patch-clamp experiments revealed that β-NAD inhibited BzATP-induced ion currents. In conclusion, we describe a novel triple membrane-passing signaling cascade triggered by extracellular β-NAD that suppresses ATP-induced release of IL-1β by monocytic cells. This cascade links activation of P2Y receptors to non-canonical metabotropic functions of nAChRs that inhibit P2X7 receptor function. The biomedical relevance of this mechanism might be the control of trauma-associated systemic inflammation. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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Review

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15 pages, 1070 KiB

Open AccessReview

Dysregulation of Adenosinergic Signaling in Systemic and Organ-Specific Autoimmunity

by Marta Vuerich, Rasika P. Harshe, Simon C. Robson and Maria Serena Longhi

Int. J. Mol. Sci. 2019, 20(3), 528; https://doi.org/10.3390/ijms20030528 - 27 Jan 2019

Cited by 17 | Viewed by 3766

Abstract

Exact causes for autoimmune diseases remain unclear and no cures are available. Breakdown of immunotolerance could set the stage for unfettered immune responses that target self-antigens. Impaired regulatory immune mechanisms could have permissive roles in autoreactivity. Abnormal regulatory immune cell function, therefore, might be a major determinant of the pathogenesis of autoimmune disease. All current treatments are associated with some level of clinical toxicity. Treatment to specifically target dysregulated immunity in these diseases would be a great advance. Extracellular adenosine is a signaling mediator that suppresses inflammation through activation of P1 receptors, most active under pathological conditions. Mounting evidence has linked alterations in the generation of adenosine from extracellular nucleotides by ectonucleotidases, and associated perturbations in purinergic signaling, to the immunological disruption and loss of immunotolerance in autoimmunity. Targeted modulation of the purinergic signaling by either targeting ectonucleotidases or modulating P1 purinergic receptors could therefore restore the balance between autoreactive immune responses; and thereby allow reestablishment of immunotolerance. We review the roles of CD39 and CD73 ectoenzymes in inflammatory states and with the dysregulation of P1 receptor signaling in systemic and organ-specific autoimmunity. Correction of such perturbations could be exploited in potential therapeutic applications. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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23 pages, 973 KiB

Open AccessReview

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

by Kevin Sek, Christina Mølck, Gregory D. Stewart, Lev Kats, Phillip K. Darcy and Paul A. Beavis

Int. J. Mol. Sci. 2018, 19(12), 3837; https://doi.org/10.3390/ijms19123837 - 02 Dec 2018

Cited by 138 | Viewed by 15345

Abstract

The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of ‘checkpoint blockade’ and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient’s own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function. The production of extracellular adenosine is mediated by the cell surface ectoenzymes CD73, CD39, and CD38 and therapeutic agents have been developed to target these as well as the downstream adenosine receptors (A₁R, A_2AR, A_2BR, A₃R) to enhance anti-tumor immune responses. This review will discuss the role of adenosine and adenosine receptor signaling in tumor and immune cells with a focus on their cell-specific function and their potential as targets in cancer immunotherapy. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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29 pages, 891 KiB

Open AccessReview

Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors

by Mercedes Garcia-Gil, Marcella Camici, Simone Allegrini, Rossana Pesi, Edoardo Petrotto and Maria Grazia Tozzi

Int. J. Mol. Sci. 2018, 19(11), 3598; https://doi.org/10.3390/ijms19113598 - 14 Nov 2018

Cited by 39 | Viewed by 9533

Abstract

The growing evidence of the involvement of purine compounds in signaling, of nucleotide imbalance in tumorigenesis, the discovery of purinosome and its regulation, cast new light on purine metabolism, indicating that well known biochemical pathways may still surprise. Adenosine deaminase is important not only to preserve functionality of immune system but also to ensure a correct development and function of central nervous system, probably because its activity regulates the extracellular concentration of adenosine and therefore its function in brain. A lot of work has been done on extracellular 5′-nucleotidase and its involvement in the purinergic signaling, but also intracellular nucleotidases, which regulate the purine nucleotide homeostasis, play unexpected roles, not only in tumorigenesis but also in brain function. Hypoxanthine guanine phosphoribosyl transferase (HPRT) appears to have a role in the purinosome formation and, therefore, in the regulation of purine synthesis rate during cell cycle with implications in brain development and tumors. The final product of purine catabolism, uric acid, also plays a recently highlighted novel role. In this review, we discuss the molecular mechanisms underlying the pathological manifestations of purine dysmetabolisms, focusing on the newly described/hypothesized roles of cytosolic 5′-nucleotidase II, adenosine kinase, adenosine deaminase, HPRT, and xanthine oxidase. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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13 pages, 638 KiB

Open AccessReview

ATP as a Pathophysiologic Mediator of Bacteria-Host Crosstalk in the Gastrointestinal Tract

by Akie Inami, Hiroshi Kiyono and Yosuke Kurashima

Int. J. Mol. Sci. 2018, 19(8), 2371; https://doi.org/10.3390/ijms19082371 - 12 Aug 2018

Cited by 26 | Viewed by 5260

Abstract

Extracellular nucleotides, such as adenosine triphosphate (ATP), are released from host cells including nerve termini, immune cells, injured or dead cells, and the commensal bacteria that reside in the gut lumen. Extracellular ATP interacts with the host through purinergic receptors, and promotes intercellular and bacteria-host communication to maintain the tissue homeostasis. However, the release of massive concentrations of ATP into extracellular compartments initiates acute and chronic inflammatory responses through the activation of immunocompetent cells (e.g., T cells, macrophages, and mast cells). In this review, we focus on the functions of ATP as a pathophysiologic mediator that is required for the induction and resolution of inflammation and inter-species communication. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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16 pages, 10191 KiB

Open AccessReview

Mechanisms of ATP Release by Inflammatory Cells

by Michel Dosch, Joël Gerber, Fadi Jebbawi and Guido Beldi

Int. J. Mol. Sci. 2018, 19(4), 1222; https://doi.org/10.3390/ijms19041222 - 18 Apr 2018

Cited by 172 | Viewed by 9100

Abstract

Extracellular nucleotides (e.g., ATP, ADP, UTP, UDP) released by inflammatory cells interact with specific purinergic P2 type receptors to modulate their recruitment and activation. The focus of this review is on stimuli and mechanisms of extracellular nucleotide release and its consequences during inflammation. Necrosis leads to non-specific release of nucleotides, whereas specific release mechanisms include vesicular exocytosis and channel-mediated release via connexin or pannexin hemichannels. These release mechanisms allow stimulated inflammatory cells such as macrophages, neutrophils, and endothelial cells to fine-tune autocrine/paracrine responses during acute and chronic inflammation. Key effector functions of inflammatory cells are therefore regulated by purinergic signaling in acute and chronic diseases, making extracellular nucleotide release a promising target for the development of new therapies. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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19 pages, 25914 KiB

Open AccessReview

Excessive Extracellular ATP Desensitizes P2Y2 and P2X4 ATP Receptors Provoking Surfactant Impairment Ending in Ventilation-Induced Lung Injury

by Djo Hasan, Joshua Satalin, Philip Van der Zee, Michaela Kollisch-Singule, Paul Blankman, Atsuko Shono, Peter Somhorst, Corstiaan Den Uil, Han Meeder, Toru Kotani and Gary F. Nieman

Int. J. Mol. Sci. 2018, 19(4), 1185; https://doi.org/10.3390/ijms19041185 - 13 Apr 2018

Cited by 20 | Viewed by 5482

Abstract

Stretching the alveolar epithelial type I (AT I) cells controls the intercellular signaling for the exocytosis of surfactant by the AT II cells through the extracellular release of adenosine triphosphate (ATP) (purinergic signaling). Extracellular ATP is cleared by extracellular ATPases, maintaining its homeostasis and enabling the lung to adapt the exocytosis of surfactant to the demand. Vigorous deformation of the AT I cells by high mechanical power ventilation causes a massive release of extracellular ATP beyond the clearance capacity of the extracellular ATPases. When extracellular ATP reaches levels >100 μM, the ATP receptors of the AT II cells become desensitized and surfactant impairment is initiated. The resulting alteration in viscoelastic properties and in alveolar opening and collapse time-constants leads to alveolar collapse and the redistribution of inspired air from the alveoli to the alveolar ducts, which become pathologically dilated. The collapsed alveoli connected to these dilated alveolar ducts are subject to a massive strain, exacerbating the ATP release. After reaching concentrations >300 μM extracellular ATP acts as a danger-associated molecular pattern, causing capillary leakage, alveolar space edema, and further deactivation of surfactant by serum proteins. Decreasing the tidal volume to 6 mL/kg or less at this stage cannot prevent further lung injury. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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21 pages, 8978 KiB

Open AccessReview

Targeting the Adenosinergic Axis in Chronic Lymphocytic Leukemia: A Way to Disrupt the Tumor Niche?

by Tiziana Vaisitti, Francesca Arruga and Silvia Deaglio

Int. J. Mol. Sci. 2018, 19(4), 1167; https://doi.org/10.3390/ijms19041167 - 12 Apr 2018

Cited by 8 | Viewed by 5300

Abstract

Targeting adenosine triphosphate (ATP) metabolism and adenosinergic signaling in cancer is gaining momentum, as increasing evidence is showing their relevance in tumor immunology and biology. Chronic lymphocytic leukemia (CLL) results from the expansion of a population of mature B cells that progressively occupies the bone marrow (BM), the blood, and peripheral lymphoid organs. Notwithstanding significant progress in the treatment of these patients, the cure remains an unmet clinical need, suggesting that novel drugs or drug combinations are needed. A unique feature of CLL is its reliance on micro-environmental signals for proliferation and cell survival. We and others have shown that the lymphoid niche, an area of intense interactions between leukemic and bystander non-tumor cells, is a typically hypoxic environment. Here adenosine is generated by leukemic cells, as well as by cells of myeloid origin, acting through autocrine and paracrine mechanisms, ultimately affecting tumor growth, limiting drug responses, and skewing the immune cells towards a tolerant phenotype. Hence, understanding the mechanisms through which this complex network of enzymes, receptors, and metabolites functions in CLL, will pave the way to the use of pharmacological agents targeting the system, which, in combination with drugs targeting leukemic cells, may get us one step closer to curing these patients. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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31 pages, 2781 KiB

Open AccessReview

ABC Transporters and Their Role in the Neoadjuvant Treatment of Esophageal Cancer

by David Vrana, Viktor Hlavac, Veronika Brynychova, Radka Vaclavikova, Cestmir Neoral, Jiri Vrba, Rene Aujesky, Marcel Matzenauer, Bohuslav Melichar and Pavel Soucek

Int. J. Mol. Sci. 2018, 19(3), 868; https://doi.org/10.3390/ijms19030868 - 15 Mar 2018

Cited by 26 | Viewed by 8010

Abstract

The prognosis of esophageal cancer (EC) is poor, despite considerable effort of both experimental scientists and clinicians. The tri-modality treatment consisting of neoadjuvant chemoradiation followed by surgery has remained the gold standard over decades, unfortunately, without significant progress in recent years. Suitable prognostic factors indicating which patients will benefit from this tri-modality treatment are missing. Some patients rapidly progress on the neoadjuvant chemoradiotherapy, which is thus useless and sometimes even harmful. At the same time, other patients achieve complete remission on neoadjuvant chemoradiotherapy and subsequent surgery may increase their risk of morbidity and mortality. The prognosis of patients ranges from excellent to extremely poor. Considering these differences, the role of drug metabolizing enzymes and transporters, among other factors, in the EC response to chemotherapy may be more important compared, for example, with pancreatic cancer where all patients progress on chemotherapy regardless of the treatment or disease stage. This review surveys published literature describing the potential role of ATP-binding cassette transporters, the genetic polymorphisms, epigenetic regulations, and phenotypic changes in the prognosis and therapy of EC. The review provides knowledge base for further research of potential predictive biomarkers that will allow the stratification of patients into defined groups for optimal therapeutic outcome. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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14 pages, 726 KiB

Open AccessReview

The Inside Story of Adenosine

by Marcella Camici, Mercedes Garcia-Gil and Maria Grazia Tozzi

Int. J. Mol. Sci. 2018, 19(3), 784; https://doi.org/10.3390/ijms19030784 - 09 Mar 2018

Cited by 52 | Viewed by 6287

Abstract

Several physiological functions of adenosine (Ado) appear to be mediated by four G protein-coupled Ado receptors. Ado is produced extracellularly from the catabolism of the excreted ATP, or intracellularly from AMP, and then released through its transporter. High level of intracellular Ado occurs only at low energy charge, as an intermediate of ATP breakdown, leading to hypoxanthine production. AMP, the direct precursor of Ado, is now considered as an important stress signal inside cell triggering metabolic regulation through activation of a specific AMP-dependent protein kinase. Intracellular Ado produced from AMP by allosterically regulated nucleotidases can be regarded as a stress signal as well. To study the receptor-independent effects of Ado, several experimental approaches have been proposed, such as inhibition or silencing of key enzymes of Ado metabolism, knockdown of Ado receptors in animals, the use of antagonists, or cell treatment with deoxyadenosine, which is substrate of the enzymes acting on Ado, but is unable to interact with Ado receptors. In this way, it was demonstrated that, among other functions, intracellular Ado modulates angiogenesis by regulating promoter methylation, induces hypothermia, promotes apoptosis in sympathetic neurons, and, in the case of oxygen and glucose deprivation, exerts a cytoprotective effect by replenishing the ATP pool. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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20 pages, 985 KiB

Open AccessReview

Unfolding Role of a Danger Molecule Adenosine Signaling in Modulation of Microbial Infection and Host Cell Response

by Jaden S. Lee and Özlem Yilmaz

Int. J. Mol. Sci. 2018, 19(1), 199; https://doi.org/10.3390/ijms19010199 - 09 Jan 2018

Cited by 16 | Viewed by 6134

Abstract

Ectonucleotidases CD39 and CD73, specific nucleotide metabolizing enzymes located on the surface of the host, can convert a pro-inflammatory environment driven by a danger molecule extracellular-ATP to an adenosine-mediated anti-inflammatory milieu. Accordingly, CD39/CD73 signaling has been strongly implicated in modulating the intensity, duration, and composition of purinergic danger signals delivered to host. Recent studies have eluted potential roles for CD39 and CD73 in selective triggering of a variety of host immune cells and molecules in the presence of pathogenic microorganisms or microbial virulence molecules. Growing evidence also suggests that CD39 and CD73 present complimentary, but likely differential, actions against pathogens to shape the course and severity of microbial infection as well as the associated immune response. Similarly, adenosine receptors A_2A and A_2B have been proposed to be major immunomodulators of adenosine signaling during chronic inflammatory conditions induced by opportunistic pathogens, such as oral colonizer Porphyromonas gingivalis. Therefore, we here review the recent studies that demonstrate how complex network of molecules in the extracellular adenosine signaling machinery and their interactions can reshape immune responses and may also be targeted by opportunistic pathogens to establish successful colonization in human mucosal tissues and modulate the host immune response. Full article

(This article belongs to the Special Issue Purinergic Signalling in Cancer and Inflammation)

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