Extracellular ATP signaling and clinical relevance

Dou, Liping; Chen, Yifa; Cowan, Peter J.; Chen, Xiaoping

doi:10.1016/j.clim.2017.12.006

Cited by 44 publications

(35 citation statements)

References 114 publications

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“…Taken together, these findings support that elevated IL-6 in TME may play an important role in pathogenesis and progression of NPC. Extracellular ATP plays a critical role in coordinating appropriate inflammatory/immune responses in various pathological processes by acting on various types of immune cells [37]. The ectoenzymes CD73 can dephosphorylate extracellular ATP to adenosine, which has potent immunosuppressive and anti-inflammatory functions, thus contributing to the establishment of tumor immunosuppressive microenvironment (TIME) [21,22].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem/stromal cells-derived IL-6 promotes nasopharyngeal carcinoma growth and resistance to cisplatin via upregulating CD73 expression

Zeng

Chen

et al. 2020

J. Cancer

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Previous studies have implicated the important role of mesenchymal stem/stromal cells (MSCs) within tumor microenvironment (TME) in the pathogenesis and progression of nasopharyngeal carcinoma (NPC), but the potential mechanisms are still unclear. Herein, we showed that an elevated IL-6 level was positively correlated with elevated expression of CD73 in TME of NPC. NPC specimens with an IL-6 high CD73 high phenotype showed higher expression levels of gp80, gp130, p-STAT3, MMP-9 and α-SMA, and clinically, a poorer prognosis than those with an IL-6 low CD73 low phenotype. We found that stimulation with conditioned media derived from IL-6 gene knocked out MSC (MSC IL6KO-CM) down-regulated the expression of CD73, IL-6, gp80, p-STAT3, and proliferative cell nuclear antigen (PCNA) in CNE-2 NPC cells. Meanwhile, NPC cells co-cultured with MSC IL6KO-CM were more sensitive to cisplatin than those co-cultured with MSC-CM. Additionally, MSC-derived IL-6 transcriptionally upregulated CD73 expression via activating STAT3 signaling pathway in NPC cells. In summary, our findings suggest that MSCs promote NPC progression and chemoresistance by upregulation of CD73 expression via activating STAT3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal stem/stromal cells-derived IL-6 promotes nasopharyngeal carcinoma growth and resistance to cisplatin via upregulating CD73 expression

Zeng

Chen

et al. 2020

J. Cancer

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“…Adenosine triphosphate (ATP) is one of the most important members of this family of molecules. However, it is well known that this ubiquitous intracellular molecular energy source, when secreted from cells, becomes an important signaling molecule and mediator of purinergic signaling ( 34 – 36 ). The release of ATP from cells in the BM microenvironment provides a molecular basis, involving activation of the ComC, for the link between purinergic signaling and activation of the innate immune response.…”

Section: Introductionmentioning

confidence: 99%

The Emerging Link Between the Complement Cascade and Purinergic Signaling in Stress Hematopoiesis

et al. 2018

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Innate immunity plays an important role in orchestrating the immune response, and the complement cascade (ComC) is a major component of this ancient defense system, which is activated by the classical-, alternative-, or mannan-binding lectin (MBL) pathways. However, the MBL-dependent ComC-activation pathway has been somewhat underappreciated for many years; recent evidence indicates that it plays a crucial role in regulating the trafficking of hematopoietic stem/progenitor cells (HSPCs) by promoting their egress from bone marrow (BM) into peripheral blood (PB). This process is initiated by the release of danger-associated molecular patterns (DAMPs) from BM cells, including the most abundant member of this family, adenosine triphosphate (ATP). This nucleotide is well known as a ubiquitous intracellular molecular energy source, but when secreted becomes an important extracellular nucleotide signaling molecule and mediator of purinergic signaling. What is important for the topic of this review, ATP released from BM cells is recognized as a DAMP by MBL, and the MBL-dependent pathway of ComC activation induces a state of “sterile inflammation” in the BM microenvironment. This activation of the ComC by MBL leads to the release of several potent mediators, including the anaphylatoxins C5a and desArgC5a, which are crucial for egress of HSPCs into the circulation. In parallel, as a ligand for purinergic receptors, ATP affects mobilization of HSPCs by activating other pro-mobilizing pathways. This emerging link between the release of ATP, which on the one hand is an activator of the MBL pathway of the ComC and on the other hand is a purinergic signaling molecule, will be discussed in this review. This mechanism plays an important role in triggering defense mechanisms in response to tissue/organ injury but may also have a negative impact by triggering autoimmune disorders, aging of HSPCs, induction of myelodysplasia, and graft-versus-host disease after transplantation of histoincompatible hematopoietic cells.

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“…Membrane preparations expressing human NTPDase1, -2, -3, or -8, respectively, were obtained as previously described (Sevigny et al, 1997;Cogan et al, 1999;Kukulski et al, 2005;Lecka et al, 2013;Lee et al, 2018). Enzyme inhibition assays were performed using the malachite green assay in analogy to published procedures with some modifications (Dou et al, 2018). The reaction buffer contained 10 mM HEPES, 2 mM CaCl 2 , and 1 mM MgCl 2 (pH 7.4) in a final volume of 50 mL in transparent 96well half-area plates.…”

Section: Malachite Green Assay To Investigate Ntpdase Inhibitorsmentioning

confidence: 99%

“…Ectonucleotidases are membrane-bound metalloenzymes that affect extracellular nucleotide and nucleoside levels by catalyzing the hydrolysis of nucleotides to the corresponding nucleosides releasing inorganic phosphate or diphosphate (Dou et al, 2018;Le et al, 2019;Vuerich et al, 2019). There are four major subfamilies of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), the ectonucleotide pyrophosphatases/phosphodiesterases (NPPs), the alkaline phosphatases (APs), and the ecto-5′-nucleotidase (ecto-5′-NT, CD73) (Bonan, 2012;Al-Rashida and Iqbal, 2015;Baqi, 2015;Fiene et al, 2016;Le et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Development of Anthraquinone Derivatives as Ectonucleoside Triphosphate Diphosphohydrolase (NTPDase) Inhibitors With Selectivity for NTPDase2 and NTPDase3

et al. 2020

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Ectonucleoside triphosphate diphosphohydrolases (NTPDases) catalyze the hydrolysis of nucleoside tri-and di-phosphates to mono-phosphates. The products are subsequently hydrolyzed by ecto-5′-nucleotidase (ecto-5′-NT) to nucleosides. NTPDase inhibitors have potential as novel drugs, e.g., for the treatment of inflammation, neurodegenerative diseases, and cancer. In this context, a series of anthraquinone derivatives structurally related to the anthraquinone dye reactive blue-2 (RB-2) was synthesized and evaluated as inhibitors of human NTPDases utilizing a malachite green assay. We identified several potent and selective inhibitors of human NTPDase2 and-3. Among the most potent NTPDase2 inhibitors were 1-amino-4-(9-phenanthrylamino)-9,10-dioxo-9,10-dihydroanthracene-2sulfonate (20, PSB-16131, IC 50 of 539 nM) and 1-amino-4-(3-chloro-4-phenylsulfanyl) phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (48, PSB-2020, IC 50 of 551 nM). The most potent NTPDase3 inhibitors were 1-amino-4-[3-(4,6-dichlorotriazin-2ylamino)-4-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (42, PSB-1011, IC 50 of 390 nM) and 1-amino-4-(3-carboxy-4-hydroxyphenylamino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (33, PSB-2046, IC 50 of 723 nM). The best NTPDase2 inhibitor 20 showed a non-competitive inhibition type, while the NTPDase3 inhibitor 42 behaved as a mixed-type inhibitor. These potent compounds were found to be selective vs. other NTPDases. They will be useful tools for studying the roles of NTPDase2 and-3 in physiology and under pathological conditions.

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Extracellular ATP signaling and clinical relevance

Cited by 44 publications

References 114 publications

Mesenchymal stem/stromal cells-derived IL-6 promotes nasopharyngeal carcinoma growth and resistance to cisplatin via upregulating CD73 expression

Mesenchymal stem/stromal cells-derived IL-6 promotes nasopharyngeal carcinoma growth and resistance to cisplatin via upregulating CD73 expression

The Emerging Link Between the Complement Cascade and Purinergic Signaling in Stress Hematopoiesis

Development of Anthraquinone Derivatives as Ectonucleoside Triphosphate Diphosphohydrolase (NTPDase) Inhibitors With Selectivity for NTPDase2 and NTPDase3

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