ADP secreted by dying melanoma cells mediates chemotaxis and chemokine secretion of macrophages via the purinergic receptor P2Y12

Kloss, Loreen; Dollt, Claudia; Schledzewski, Kai; Krewer, Andreas; Melchers, Susanne; Manta, Calin; Sticht, Carsten; Torre, Carolina De La; Utikal, Jochen; Umansky, Viktor; Schmieder, Astrid

doi:10.1038/s41419-019-2010-6

Cited by 25 publications

(17 citation statements)

References 43 publications

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“…It has been well-established in literature that the levels of ATP increase in the tumor microenvironment ( Idzko et al, 2014 ; Di Virgilio et al, 2018 ). This is especially true in the case of cancers that are therapeutically targeted wherein death of drug- or radiation-sensitive cells results in changing the contents of the microenvironment, of which ATP, among others, is a prominent molecule ( Martins et al, 2009 ; Schneider et al, 2015 ; Kloss et al, 2019 ). We observed that the treatment with doxorubicin also showed an increase in the levels of eATP in the media 48 h post-stimulation.…”

Section: Discussionmentioning

confidence: 99%

Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2

2021

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The tumor microenvironment plays a major role in the ability of the tumor cells to undergo metastasis. A major player of tumors gaining metastatic property is the inflammatory protein, cyclooxygenase 2 (COX-2). Several tumors show upregulation of this protein, which has been implicated in mediating metastasis in various cancer types such as of colon, breast and lung. In this report, we show that the concentration of extracellular ATP (eATP) is increased in response to cell death mediated by chemotherapeutic agents such as doxorubicin. By using three different cell-lines—HeLa (cervical), IMR-32 (neuronal) and MCF-7 (breast)—we show that this eATP goes on to act on purinergic (P2) receptors. Among the various P2 receptors expressed in these cells we identified P2X7, in IMR-32 and MCF-7 cells, and P2Y12, in HeLa cells, as important in modulating cell migration and invasion. Downstream of the P2 receptor activation, both p42/44 mitogen-activated protein kinase (MAPK) and the p38 MAPK are activated in these cells. These result in an increase in the expression of COX-2 mRNA and protein. We also observe an increase in the activity of matrix metalloproteinase 2 (MMP-2) enzyme in these cells. Blocking the P2 receptors not only blocks migration and invasion, but also COX-2 synthesis and MMP-2 activity. Our results show the link between purinergic receptors and COX-2 expression. Increased levels of ATP in the tumor microenvironment, therefore, leads to increased COX-2 expression, which, in turn, affords migratory and invasive properties to the tumor. This provides P2 receptor-based anti-inflammatory drugs (PBAIDs) a potential opportunity to be explored as cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2

2021

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“…33 The purinergic G-protein coupled receptor P2RY12 is a therapeutic target of the clinically approved anti-thrombotic drugs cangrelor and clopidogrel. 34 Kloss et al 34 demonstrated that P2RY12 activation triggers the migration of macrophages to necrotic tumor areas and modulates chemotaxis and the chemokine secretion of macrophages. Our research revealed that the genes for all four of these proteins (P2RY12, GP6, GP9, and GP1BA) were upregulated in PD samples in the GSE49126 and GSE100054 datasets, although only GP1BA and GP6 were upregulated in our clinical cohort of PD patients.…”

Section: Discussionmentioning

confidence: 99%

“… 33 The purinergic G-protein coupled receptor P2RY12 is a therapeutic target of the clinically approved anti-thrombotic drugs cangrelor and clopidogrel. 34 Kloss et al. 34 demonstrated that P2RY12 activation triggers the migration of macrophages to necrotic tumor areas and modulates chemotaxis and the chemokine secretion of macrophages.…”

Section: Discussionmentioning

confidence: 99%

Identification of Parkinson’s disease-related pathways and potential risk factors

Shen

Chen

et al. 2020

J Int Med Res

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Objective To identify Parkinson’s disease (PD)-associated deregulated pathways and genes, to further elucidate the pathogenesis of PD. Methods Dataset GSE100054 was downloaded from the Gene Expression Omnibus, and differentially expressed genes (DEGs) in PD samples were identified. Functional enrichment analyses were conducted for the DEGs. The top 10 hub genes in the protein–protein interaction (PPI) network were screened out and used to construct a support vector machine (SVM) model. The expression of the top 10 genes was then validated in another dataset, GSE46129, and a clinical patient cohort. Results A total of 333 DEGs were identified. The DEGs were clustered into two gene sets that were significantly enriched in 12 pathways, of which 8 were significantly deregulated in PD, including cytokine–cytokine receptor interaction, gap junction, and actin cytoskeleton regulation. The signature of the top 10 hub genes in the PPI network was used to construct the SVM model, which had high performance for predicting PD. Of the 10 genes, GP1BA, GP6, ITGB5, and P2RY12 were independent risk factors of PD. Conclusion Genes such as GP1BA, GP6, P2RY12, and ITGB5 play critical roles in PD pathology through pathways including cytokine−cytokine receptor interaction, gap junctions, and actin cytoskeleton regulation.

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“…P2Y 12 receptor protein expression has also been verified. Such macrophages display a phenotype similar to that of tumor-associated macrophages (TAM) [ 110 ]. In the same work, P2Y 12 expression was confirmed on CD163-expressing TAM of melanoma in situ.…”

Section: P2y 12 Receptormentioning

confidence: 99%

“…Pharmacological inhibition of P2Y 12 receptor was found to evoke an endoplasmic reticulum (ER) stress response that appears to block M2 markers such as arginase-1, indicative of a shift towards M1 [ 109 ]. Similar to the P2Y 2 receptor on macrophages, which senses ATP and UTP released from apoptotic cells [ 55 ], the P2Y 12 receptor has been reported to direct migration of TAM towards ADP-releasing melanoma cells in necrotic tumor areas [ 110 ]. In recombinant U937 cells, stimulation of ectopic P2Y 12 receptor with ADP induced the secretion of chemokines including CXCL8 [ 110 ].…”

Section: P2y 12 Receptormentioning

confidence: 99%

Control of Macrophage Inflammation by P2Y Purinergic Receptors

Klaver

Thurnher

2021

Cells

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Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy.

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ADP secreted by dying melanoma cells mediates chemotaxis and chemokine secretion of macrophages via the purinergic receptor P2Y12

Cited by 25 publications

References 43 publications

Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2

Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2

Identification of Parkinson’s disease-related pathways and potential risk factors

Control of Macrophage Inflammation by P2Y Purinergic Receptors

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