Inorganic Chemical Pollutants
William J. Rea, Kalpana D. Patel in Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
In addition to acting as a calcium channel blocker, gadolinium, at low concentration, can interact with the signaling involved in intracellular and extracellular ATP hydrolysis.589 Escalada et al.590 reported that 3 μM gadolinium, a concentration that does not block calcium channels, has a potent inhibitory action on ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) activity from the electric organ of Torpedo marmorata. Extracellular nucleotides are important molecules involved in the regulation of different biological processes, including vascular tone. When released as a neurotransmitter from the sympathetic terminals, ATP binds to P2X receptors of vascular smooth muscle cells, producing vasoconstriction. When binding to endothelial P2Y receptors, ATP leads to vasodilatation.589,591 ATP exerts other effects on the vascular beds, such as control of smooth muscle and endothelial cell proliferation.589,591 The action of extracellular nucleotides is terminated by the E-NTPDase family. NTPDase 1 is the major ectonucleotidase expressed in the vasculature589,591 and its action limits platelet activation by ATP hydrolysis.589,591 NTPDase 2 is another ectonucleotidase associated with the vasculature that preferentially converts ATP to ADP.592 Following the action of E-NTPDases, ecto-5′-nucleotidase is responsible for the end of nucleotide signaling by converting AMP to adenosine.593
Cell and Extracellular Matrix Interactions in a Dynamic Biomechanical Environment:
Michel R. Labrosse in Cardiovascular Mechanics, 2018
Pathological cyclic stretch also works in concert with TGF-β1 to promote more collagen synthesis and αSMA expression than TGF-β1 or stretch alone (Merryman et al. 2007). Stretched VIC monolayers treated with TGF-β1 developed nodules that began as aggregates of apoptotic cells before developing into a necrotic core surrounded by apoptotic cells, mirroring dystrophic calcification (Fisher et al. 2013). Interestingly, cyclic stretch plays a key role in nodule growth by preventing cells from migrating out of the nodule. While Fisher proposed that the initiating event for apoptosis might be mechanical damage, cyclic stretch also promotes apoptotic cell signaling directly (Bouchareb et al. 2014). Pathological cyclic stretch increases ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), an ectonucleotidase enzyme, which causes apoptosis in VICs in vitro through a process that includes the formation of spheroid microparticles rich in calcium and phosphorus. These microparticles have been found in diseased valves colocalized with high ENPP1. Mechanical control of ENPP1 transport to the cell surface, its site of action, is controlled by the Rho/ROCK pathway, where ROCK inhibition prevents ENPP1 localization and stretch-induced mineralization.
Role of Blood Coagulation-Fibrinolytic System and Endothelial Cells in Malignancy
László Muszbek in Hemostasis and Cancer, 2019
Besides, endothelial cells have other components either with anticoagulant character or with fibrinolytic activity. Several types of cells synthesize sulfated mucopolysaccharides, but only endothelial cells secrete a species of heparan sulfate with anticoagulant activity.36 Heparin also binds to endothelial cells,37 and this interaction may influence thrombin functions. Another mechanism by which endothelium is related to the resistance to thrombogenesis is the presence of an ectonucleotidase system on the cells, namely, nucleoside triphosphatase, diphosphatase, and 5′-nucleotidase catabolized ATP, ADP, and AMP, leading to adenosine formation.38,39 The reactions are stimulated by thrombin.40,41 This system may play a role in hemostasis, because ADP is an inducer of platelet aggregation, while adenosine is an inhibitor.42 The role of prostacycline as an anticoagulant, synthesized by endothelial cells, is discussed later. Endothelial cells contribute to the resolution of fibrin by plasmin via conversion of plasminogen by a plasminogen activator synthesized in these cells.43 The activator, with Mr 50,000, is membrane associated and is in the “latent” form intracellularly.44 While some tumor-promoting agents increase the rate of plasminogen activator production, thrombin may decrease it.45
Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism
Published in mAbs, 2020
Bradley N. Spatola, Alana G. Lerner, Clifford Wong, Tracy dela Cruz, Megan Welch, Wanchi Fung, Maria Kovalenko, Karolina Losenkova, Gennady G. Yegutkin, Courtney Beers, John Corbin, Vanessa B. Soros
An inhibitor of CD39 should be exquisitely specific, lacking reactivity to other ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) family members that regulate ATP.21 For example, NTPDase2 (CD39L1) activates platelets in the vasculature,21 and NTPDase8 is the major ectonucleotidase active in the liver.22 A disruption of either nucleotide hydrolase’s activity function by a promiscuous NTPDase inhibitor may cause undesired toxicities. Outside of the enzymes of NTPDase family, extracellular nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) and tissue-nonspecific alkaline phosphatase (TNAP) also hydrolyze ATP. However, both enzymes have reduced catalytic activity at neutral pH and are not expected to significantly contribute to ATP catabolism in the slightly acidic TME.2 The published small molecule inhibitors of CD39, such as sodium polyoxotungstate (POM-1), 6-N, N-diethyl-D-β,γ-dibromomethylene-ATP-trisodium salt (ARL-67156), adenylyl-imidophosphate (AMP-PNP), and sodium azide, are neither CD39-specific nor have favorable drug-like properties.23–29 A monoclonal antibody (mAb) inhibitor of CD39 ATPase activity would be anticipated to meet the specificity requirements for a therapeutic.
Prognostic value of CD73 expression in resected colorectal cancer liver metastasis
Published in OncoImmunology, 2020
Nouredin Messaoudi, Isabelle Cousineau, Elizabeth Arslanian, David Henault, David Stephen, Franck Vandenbroucke-Menu, Michel Dagenais, Richard Létourneau, Marylène Plasse, André Roy, Réal Lapointe, Dirk Ysebaert, Dominique Trudel, Geneviève Soucy, John Stagg, Simon Turcotte
The final step in the conversion of pro-inflammatory extracellular ATP to immunosuppressive adenosine is catalyzed by the rate-limiting membrane-bound and soluble ectonucleotidase CD73, and constitutes an important negative-feedback mechanism that prevents excessive immune responses.24 Recent evidence support that many solid tumors usurp this pathway as an immune escape mechanism. In this study, we found a broad range of intratumoral CD73 expression in CRLMs by cancer and stromal cells. High CD73 in the TME of CRLMs was associated with shorter TTR and DSS, multiple and larger metastases, and resistance to preoperative chemotherapy. Intriguingly, sCD73 was not correlated with tCD73. While sCD73 was not significantly associated with clinicopathological features, patients with higher sCD73 levels (top 7.2%) displayed shorter DSS. To our knowledge, this is the first study investigating tCD73 and sCD73 in the metastatic setting of a significantly large cohort of patients with a common epithelial malignancy.
Ectonucleotidase CD39 expression in regional metastases in head and neck cancer
Published in Acta Oto-Laryngologica, 2018
Magis Mandapathil, Mehtap Boduc, Marion Roessler, Christian Güldner, Ute Walliczek-Dworschak, Robert Mandic
The underlying mechanisms of CD39 overexpression in different types of cells, including its role in tumor progression, are not fully understood. Some studies have suggested that CD39 mediates the promotion of tumor growth and metastases by suppressing antitumor immune responses and promoting neoangiogenesis [15]. Extracellular ATP, which is effectively metabolized by CD39, directly suppresses tumor cell growth. Therefore, activity of CD39 in this setting in the tumor microenvironment already favors tumor cell growth. Further, adenosine the end product of ectonucleotidase activities has been described to mediate immunosuppressive effects in various ways, for example, suppressing effector T cell functions through adenosine 2a (A2a) receptor signaling with subsequent intracellular elevation of cycling AMP (cAMP) [7,16,17]. cAMP has been shown to be a crucial regulator of CD39 expression by acting through the PKA/CREB, PKA/PI3K/ATF2 and PKA/ERK/ATF2 pathways [18].
Related Knowledge Centers
- Adenosine Receptor
- Enzyme
- Nucleoside
- Nucleotide
- Metabolism
- Cell Membrane
- Purinergic Signalling
- Entpd1
- Nt5E