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Purine Signaling and Metabolism in Tumors

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (20 May 2021) | Viewed by 50526

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Special Issue Editor

Prof. Renata Ciccarelli

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Department of Medical, Oral and Biotechnology Sciences, Section of Pharmacology, University of Chieti-Pescara, I-66013 Chieti, Italy
Interests: glial cell function; activities of adenine and guanine-based purines as signaling molecules in the mechanisms involved in neurotransmission and neuroprotection; mesenchymal stem cell (MSC) biological characteristics; glioblastoma multiforme (GBM)-derived stem cell (GSC) properties; modulatory receptor activity of adenine-based purines on the osteogenic differentiation of normal human MSCs and on the aggressivenes of human GSCs

Special Issue Information

Dear Colleagues,

Cancer continues to be a serious health problem and one of the most common causes of mortality worldwide, despite the continued adoption of new therapeutic strategies and innovative agents. Therapeutic insufficiency is due to the enormous variety of biological processes involved in the growth of a tumor, which can coexist or activate when necessary to favor its expansion/recurrence. Furthermore, cancer cells have a remarkable ability to implement adaptive strategies to escape even the most effective treatments. Therefore, an understanding of this complex machinery and the discovery of molecules capable of hindering/contrasting the growth mechanisms of cancer is crucial, thus providing new therapeutic opportunities.

Today, there is a renewed interest in purines in oncology. They are ancestral and ubiquitous molecules present in virtually all cell types and are indispensable for the proliferation of cancer cells. Therefore, synthetic analogues of purines, which act as antimetabolites, have been and are still being used for the treatment of various cancers. However, growing evidence has highlighted that high levels of purines, in particular ATP and adenosine, are present in the tumor microenvironment, where, interacting as signal molecules with their specific receptors, they influence not only tumor growth but also tumor–host interaction and immune function in several ways. Furthermore, dysregulation of enzymes that degrade ATP/adenosine has been reported in extracellular tumor fluid. All of these results are promoting research to add new knowledge into purine receptor activity and metabolism in order to find purine receptor ligands and/or purine analogues/metabolites capable of suppressing tumor cell growth.

The purpose of this Special Issue dedicated to “Purine Signaling and Metabolism in Tumors” is to attract the interest of those scientists who are investigating the above-mentioned aspects. This Special Issue should represent an update of research on purines in oncology and hopefully gather new discoveries about these compounds to translate into new anticancer therapies.

Prof. Renata Ciccarelli
Guest Editor

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Keywords

expression of purine receptors in tumor cells/tissues
activity of purines as signaling molecules in cancer development and progression
presence and activity of purine metabolizing enzymes in cancer growth/expansion
modulation of mechanisms/molecular and enzyme pathways involved in tumor growth and recurrence by ligands for purinergic receptors and/or purine analogs

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Published Papers (9 papers)

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Research

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20 pages, 4347 KiB

Open AccessArticle

The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

by Lara Magni, Rayhana Bouazzi, Hugo Heredero Olmedilla, Patricia S. S. Petersen, Marco Tozzi and Ivana Novak

Cells 2021, 10(8), 1928; https://doi.org/10.3390/cells10081928 - 29 Jul 2021

Cited by 25 | Viewed by 3403

Abstract

Pancreatic stellate cells (PSCs) are important pancreatic fibrogenic cells that interact with pancreatic cancer cells to promote the progression of pancreatic ductal adenocarcinoma (PDAC). In the tumor microenvironment (TME), several factors such as cytokines and nucleotides contribute to this interplay. Our aim was to investigate whether there is an interaction between IL-6 and nucleotide signaling, in particular, that mediated by the ATP-sensing P2X7 receptor (P2X7R). Using human cell lines of PSCs and cancer cells, as well as primary PSCs from mice, we show that ATP is released from both PSCs and cancer cells in response to mechanical and metabolic cues that may occur in the TME, and thus activate the P2X7R. Functional studies using P2X7R agonists and inhibitors show that the receptor is involved in PSC proliferation, collagen secretion and IL-6 secretion and it promotes cancer cell migration in a human PSC-cancer cell co-culture. Moreover, conditioned media from P2X7R-stimulated PSCs activated the JAK/STAT3 signaling pathway in cancer cells. The monoclonal antibody inhibiting the IL-6 receptor, Tocilizumab, inhibited this signaling. In conclusion, we show an important mechanism between PSC-cancer cell interaction involving ATP and IL-6, activating P2X7 and IL-6 receptors, respectively, both potential therapeutic targets in PDAC. Full article

(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)

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13 pages, 1630 KiB

Open AccessArticle

Cytosolic 5′-Nucleotidase II Is a Sensor of Energy Charge and Oxidative Stress: A Possible Function as Metabolic Regulator

by Rossana Pesi, Simone Allegrini, Francesco Balestri, Mercedes Garcia-Gil, Federico Cividini, Laura Colombaioni, Lars Petter Jordheim, Marcella Camici and Maria Grazia Tozzi

Cells 2021, 10(1), 182; https://doi.org/10.3390/cells10010182 - 18 Jan 2021

Cited by 7 | Viewed by 3854

Abstract

Cytosolic 5′-nucleotidase II (NT5C2) is a highly regulated enzyme involved in the maintenance of intracellular purine and the pyrimidine compound pool. It dephosphorylates mainly IMP and GMP but is also active on AMP. This enzyme is highly expressed in tumors, and its activity correlates with a high rate of proliferation. In this paper, we show that the recombinant purified NT5C2, in the presence of a physiological concentration of the inhibitor inorganic phosphate, is very sensitive to changes in the adenylate energy charge, especially from 0.4 to 0.9. The enzyme appears to be very sensitive to pro-oxidant conditions; in this regard, the possible involvement of a disulphide bridge (C175-C547) was investigated by using a C547A mutant NT5C2. Two cultured cell models were used to further assess the sensitivity of the enzyme to oxidative stress conditions. NT5C2, differently from other enzyme activities, was inactivated and not rescued by dithiothreitol in a astrocytoma cell line (ADF) incubated with hydrogen peroxide. The incubation of a human lung carcinoma cell line (A549) with 2-deoxyglucose lowered the cell energy charge and impaired the interaction of NT5C2 with the ice protease-activating factor (IPAF), a protein involved in innate immunity and inflammation. Full article

(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)

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15 pages, 2631 KiB

Open AccessArticle

Inhibiting the P2X4 Receptor Suppresses Prostate Cancer Growth In Vitro and In Vivo, Suggesting a Potential Clinical Target

by Jiepei He, Yuhan Zhou, Hector M. Arredondo Carrera, Alexandria Sprules, Ramona Neagu, Sayyed Amin Zarkesh, Colby Eaton, Jian Luo, Alison Gartland and Ning Wang

Cells 2020, 9(11), 2511; https://doi.org/10.3390/cells9112511 - 20 Nov 2020

Cited by 27 | Viewed by 4662

Abstract

Prostate cancer (PCa) is the most frequently diagnosed cancer in men, causing considerable morbidity and mortality. The P2X4 receptor (P2X4R) is the most ubiquitously expressed P2X receptor in mammals and is positively associated with tumorigenesis in many cancer types. However, its involvement in PCa progression is less understood. We hypothesized that P2X4R activity enhanced tumour formation by PCa cells. We showed that P2X4R was the most highly expressed, functional P2 receptor in these cells using quantitative reverse transcription PCR (RT-PCR) and a calcium influx assay. The effect of inhibiting P2X4R on PCa (PC3 and C4-2B4 cells) viability, proliferation, migration, invasion, and apoptosis were examined using the selective P2XR4 antagonists 5-BDBD and PSB-12062. The results demonstrated that inhibiting P2X4R impaired the growth and mobility of PCa cells but not apoptosis. In BALB/c immunocompromised nude mice inoculated with human PC3 cells subcutaneously, 5-BDBD showed anti-tumourigenic effects. Finally, a retrospective analysis of P2RX4 expression in clinical datasets (GDS1439, GDS1746, and GDS3289) suggested that P2X4R was positively associated with PCa malignancy. These studies suggest that P2X4R has a role in enhancing PCa tumour formation and is a clinically targetable candidate for which inhibitors are already available and have the potential to suppress disease progression. Full article

(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)

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17 pages, 2500 KiB

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Human P2X7 Receptor Causes Cycle Arrest in RPMI-8226 Myeloma Cells to Alter the Interaction with Osteoblasts and Osteoclasts

by Ankita Agrawal, Lars S. Kruse, Annette J. Vangsted, Alison Gartland and Niklas R. Jørgensen

Cells 2020, 9(11), 2341; https://doi.org/10.3390/cells9112341 - 22 Oct 2020

Cited by 7 | Viewed by 2867

Abstract

Multiple myeloma is a malignant expansion of plasma cells and aggressively affects bone health. We show that P2X7 receptor altered myeloma growth, which affects primary bone cells in vitro. Expression on six human myeloma cell lines confirmed the heterogeneity associated with P2X7 receptor. Pharmacology with 2′(3′)-O-(4-benzoylbenzoyl) adenosine 5′-triphosphate (BzATP) as agonist showed dose-dependent membranal pores on RPMI-8226 (p = 0.0027) and blockade with P2X7 receptor antagonists. Ca²⁺ influx with increasing doses of BzATP (p = 0.0040) was also inhibited with antagonists. Chronic P2X7 receptor activation reduced RPMI-8226 viability (p = 0.0208). No apoptosis or RPMI-8226 death was observed by annexin V/propidium iodide (PI) labeling and caspase-3 cleavage, respectively. However, bromodeoxyuridine (BrdU) labelling showed an accumulation of RPMI-8226 in the S phase of cell cycle progression (61.5%, p = 0.0114) with significant decline in G0/G1 (5.2%, p = 0.0086) and G2/M (23.5%, p = 0.0015) phases. As myeloma pathology depends on a positive and proximal interaction with bone, we show that P2X7 receptor on RPMI-8226 inhibited the myeloma-induced suppression on mineralization (p = 0.0286) and reversed the excessive osteoclastic resorption. Our results demonstrate a view of how myeloma cell growth is halted by P2X7 receptor and the consequences on myeloma–osteoblast and myeloma–osteoclast interaction in vitro. Full article

(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)

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15 pages, 1227 KiB

Open AccessFeature PaperReview

Cancer Metabostemness and Metabolic Reprogramming via P2X7 Receptor

by Izadora Lorrany Alves Rabelo, Vanessa Fernandes Arnaud-Sampaio, Elena Adinolfi, Henning Ulrich and Claudiana Lameu

Cells 2021, 10(7), 1782; https://doi.org/10.3390/cells10071782 - 14 Jul 2021

Cited by 19 | Viewed by 3895

Abstract

The heterogeneity of tumor cell mass and the plasticity of cancer cell phenotypes in solid tumors allow for the insurgence of resistant and metastatic cells, responsible for cancer patients’ clinical management’s main challenges. Among several factors that are responsible for increased cancer aggression, metabolic reprogramming is recently emerging as an ultimate cancer hallmark, as it is central for cancer cell survival and self-renewal, metastasis and chemoresistance. The P2X7 receptor, whose expression is upregulated in many solid and hematological malignancies, is also emerging as a good candidate in cancer metabolic reprogramming and the regulation of stem cell proliferation and differentiation. Metabostemness refers to the metabolic reprogramming of cancer cells toward less differentiated (CSCs) cellular states, and we believe that there is a strong correlation between metabostemness and P2X7 receptor functions in oncogenic processes. Here, we summarize important aspects of P2X7 receptor functions in normal and tumor tissues as well as essential aspects of its structure, regulation, pharmacology and its clinical use. Finally, we review current knowledge implicating P2X7 receptor functions in cancer-related molecular pathways, in metabolic reprogramming and in metabostemness. Full article

(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)

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16 pages, 2638 KiB

Open AccessReview

P2X7 Variants in Oncogenesis

by Anna Pegoraro, Elena De Marchi and Elena Adinolfi

Cells 2021, 10(1), 189; https://doi.org/10.3390/cells10010189 - 19 Jan 2021

Cited by 46 | Viewed by 5050

Abstract

The P2X7 receptor for extracellular ATP is a well-established mediator of tumoral development and progression both in solid cancers and hematological malignancies. The human P2X7 gene is highly polymorphic, and several splice variants of the receptor have been identified in time. P2X7 single-nucleotide polymorphisms (SNPs) have been broadly analyzed by studies relating them to pathologies as different as infectious, inflammatory, nervous, and bone diseases, among which cancer is included. Moreover, in the last years, an increasing number of reports concentrated on P2X7 splice variants’ different roles and their implications in pathological conditions, including oncogenesis. Here, we give an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions, mainly focusing on current data emerging on P2X7 isoform B and nfP2X7. We explored the role of these and other genetic variants of P2X7 in cancer insurgence, dissemination, and progression, as well as the effect of chemotherapy on isoforms expression. The described literature strongly suggests that P2X7 variants are potential new biomarkers and therapeutical targets in oncological conditions and that their study in carcinogenesis deserves to be further pursued. Full article

(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)

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15 pages, 316 KiB

Open AccessReview

Adenine-Based Purines and Related Metabolizing Enzymes: Evidence for Their Impact on Tumor Extracellular Vesicle Activities

by Patrizia Di Iorio and Renata Ciccarelli

Cells 2021, 10(1), 188; https://doi.org/10.3390/cells10010188 - 19 Jan 2021

Cited by 4 | Viewed by 3370

Abstract

Extracellular vesicles (EVs), mainly classified as small and large EVs according to their size/origin, contribute as multi-signal messengers to intercellular communications in normal/pathological conditions. EVs are now recognized as critical players in cancer processes by promoting transformation, growth, invasion, and drug-resistance of tumor cells thanks to the release of molecules contained inside them (i.e., nucleic acids, lipids and proteins) into the tumor microenvironment (TME). Interestingly, secretion from donor cells and/or uptake of EVs/their content by recipient cells are regulated by extracellular signals present in TME. Among those able to modulate the EV-tumor crosstalk, purines, mainly the adenine-based ones, could be included. Indeed, TME is characterized by high levels of ATP/adenosine and by the presence of enzymes deputed to their turnover. Moreover, ATP/adenosine, interacting with their own receptors, can affect both host and tumor responses. However, studies on whether/how the purinergic system behaves as a modulator of EV biogenesis, release and functions in cancer are still poor. Thus, this review is aimed at collecting data so far obtained to stimulate further research in this regard. Hopefully, new findings on the impact of adenine purines/related enzymes on EV functions may be exploited in tumor management uncovering novel tumor biomarkers and/or druggable targets. Full article

(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)

22 pages, 5206 KiB

Open AccessReview

Extracellular ATP: A Feasible Target for Cancer Therapy

by Valentina Vultaggio-Poma, Alba Clara Sarti and Francesco Di Virgilio

Cells 2020, 9(11), 2496; https://doi.org/10.3390/cells9112496 - 17 Nov 2020

Cited by 176 | Viewed by 12148

Abstract

Adenosine triphosphate (ATP) is one of the main biochemical components of the tumor microenvironment (TME), where it can promote tumor progression or tumor suppression depending on its concentration and on the specific ecto-nucleotidases and receptors expressed by immune and cancer cells. ATP can be released from cells via both specific and nonspecific pathways. A non-regulated release occurs from dying and damaged cells, whereas active release involves exocytotic granules, plasma membrane-derived microvesicles, specific ATP-binding cassette (ABC) transporters and membrane channels (connexin hemichannels, pannexin 1 (PANX1), calcium homeostasis modulator 1 (CALHM1), volume-regulated anion channels (VRACs) and maxi-anion channels (MACs)). Extracellular ATP acts at P2 purinergic receptors, among which P2X7R is a key mediator of the final ATP-dependent biological effects. Over the years, P2 receptor- or ecto-nucleotidase-targeting for cancer therapy has been proposed and actively investigated, while comparatively fewer studies have explored the suitability of TME ATP as a target. In this review, we briefly summarize the available evidence suggesting that TME ATP has a central role in determining tumor fate and is, therefore, a suitable target for cancer therapy. Full article

(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)

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24 pages, 1943 KiB

Open AccessReview

Purinergic Signaling in the Hallmarks of Cancer

by Anaí del Rocío Campos-Contreras, Mauricio Díaz-Muñoz and Francisco G. Vázquez-Cuevas

Cells 2020, 9(7), 1612; https://doi.org/10.3390/cells9071612 - 3 Jul 2020

Cited by 67 | Viewed by 10046

Abstract

Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments. Full article

(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)

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