The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma

Amoroso, Francesca; Capece, Marina; Rotondo, Alessandra; Cangelosi, Davide; Ferracin, Manuela; Franceschini, Alessia; Raffaghello, Lizzia; Pistoia, Vito; Varesio, Luigi; Adinolfi, Elena

doi:10.1038/onc.2014.444

Cited by 154 publications

(197 citation statements)

References 51 publications

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“…P2X7R expression and activity, which has been reported in several cancers, has been suggested as a potential cancer cell biomarker (Baricordi et al, 1999;Adinolfi et al, 2012;Amoroso et al, 2015). However, the role of P2X7R in oncology is still unclear, and two opposite hypothesis have been proposed.…”

Section: The Ionotropic Atp-gated P2x7 Receptormentioning

confidence: 95%

“…In the tumor microenvironment, ATP acts as a trophic factor, a danger signal, and the main source of the immunosuppressant adenosine (Amoroso et al, 2015). High levels of extracellular ATP can inhibit proliferation and induce apoptosis/necrosis in mouse GL261 cells and in human M059J glioma cells (Tamajusuku et al, 2010;Gehring et al, 2012Gehring et al, , 2015Bian et al, 2013).…”

Section: The Ionotropic Atp-gated P2x7 Receptormentioning

confidence: 99%

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Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy

Morrone¹,

Gehring²,

Nicoletti³

2016

Mol Pharmacol

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Malignant brain tumors are highly lethal and aggressive. Despite recent advances in the current therapies, which include the combination of surgery and radio/chemotherapy, the average survival rate remains poor. Altered regulation of ion channels is part of the neoplastic transformation, which suggests that ion channels are involved in cancer. Distinct classes of calciumpermeable channels are abnormally expressed in cancer and are likely involved in the alterations underlying malignant growth. Specifically, cytosolic Ca 21 activity plays an important role in the regulation of cell proliferation, and Ca 21 signaling is altered in proliferating tumor cells. A series of previous studies emphasized the importance of the T-type low-voltage-gated calcium channels (VGCC) in different cancer types, including gliomas, and remarkably, pharmacologic inhibition of T-type VGCC caused antiproliferative effects and triggered apoptosis of human glioma cells. Other calcium permeable channels, such as transient receptor potential (TRP) channels, contribute to changes in Ca 21 by modulating the driving force for Ca 21 entry, and some TRP channels are required for proliferation and migration in gliomas. Furthermore, recent evidence shows that TRP channels contribute to the progression and survival of the glioblastoma patients. Likewise, the purinergic P2X7 receptor acts as a direct conduit for Ca 21 -influx and an indirect activator of voltage-gated Ca 21 -channel. Evidence also shows that P2X7 receptor activation is linked to elevated expression of inflammation promoting factors, tumor cell migration, an increase in intracellular mobilization of Ca 21 , and membrane depolarization in gliomas. Therefore, this review summarizes the recent findings on calcium channels and associated receptors as potential targets to treat malignant gliomas.

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Section: The Ionotropic Atp-gated P2x7 Receptormentioning

confidence: 95%

Section: The Ionotropic Atp-gated P2x7 Receptormentioning

confidence: 99%

Calcium Channels and Associated Receptors in Malignant Brain Tumor Therapy

Morrone¹,

Gehring²,

Nicoletti³

2016

Mol Pharmacol

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“…Tumors induced by the implant of HEK-293 cells heterologously expressing P2X7 receptors in immunodeficient mice showed elevated growth rate, an anaplastic phenotype, and high production of VEGF a well-known EMT inductor [67]. In cell lines derived from neuroblastoma or ovarian carcinoma, P2X7 receptor activity is correlated with high tumoral growth and metastatic induction, effects that involve PI3K/ AKT pathway activity [67][68][69][70]. Moreover, in pancreatic ductal adenocarcinoma cell lines, P2X7 receptor activity regulates migration and invasion, responses associated with EMT induction [71].…”

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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“…Additional confirmations, many very recently, of the up-regulation of the receptor in cancer tissue have been obtained for pancreatic [43], lung [44], skin [45][46][47], brain [48,49], renal [38], prostate [50], thyroid [51], bone [52] and both ALL and AML [53,54].…”

Section: Discussionmentioning

confidence: 88%