A critical role of thrombin/PAR-1 in ADP-induced platelet secretion and the second wave of aggregation

Jiang, Lei; Xu, Chunlin; Yu, Shanshan; Liu, P.; Luo, Dong-Hua; Zhou, Qi; Gao, Cunji; Hu, Haitao

doi:10.1111/jth.12168

Cited by 27 publications

(17 citation statements)

References 45 publications

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“…Recently, Jiang and colleagues demonstrated that platelets activated with ADP generate thrombin, which propagates platelet activation through thrombinmediated PAR1 activation. 42 Platelets exposed to anticoagulants prior to activation with ADP also exhibit impaired thrombin/ PAR1 signaling. Therefore, PAR1 antagonists may represent a novel therapeutic target for regulation of tumor growth and metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…40,41 In addition, thrombin is also generated in response to platelet activation by the agonist adenosine 59-diphosphate (ADP), which results in subsequent activation of the PAR1 receptor. 42 Therefore, anticoagulants could impact tumor cell and platelet interaction by inhibiting thrombin and interfering with PAR-mediated platelet activation. The importance of PAR blockade in angiogenesis was previously demonstrated by Ma and colleagues, who showed that PAR1 inhibition diminished angiogenic-dependent wound healing.…”

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confidence: 99%

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Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

Battinelli

Markens

Kulenthirarajan

et al. 2014

Blood

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• Anticoagulants inhibit release of angiogenic proteins from platelets.Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 59-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential. (Blood. 2014;123(1):101-112) IntroductionCancer cells are surrounded by and interact with a complex milieu consisting of but not limited to endothelial cells, mast cells, macrophages, stromal cells, and lymphocytes. In fact, tumor cells live in intimate symbiosis with the rest of the body and appear to hijack normal physiological processes to aid their progression and growth. The recognition that tumor growth and metastasis is not exclusively an independent process for tumor cells suggests that disrupting the tumor microenvironment might provide a novel treatment modality for malignancy.Although platelets are best known for their role in hemostasis and thrombosis, a substantial amount of data supports the idea that platelets play important roles in tumorigenesis, contributing to inflammation, angiogenesis, and metastatic dissemination of tumor cells.1 Platelet count can be a prognostic factor in cancer, patients presenting with thrombocytosis having a poor survival in a variety of cancers including breast cancer.2-5 Conversely, the presence of thrombocytopenia is associated with a survival benefit and decreased metastasis.6-9 For tumors to grow beyond 1 to 2 mm 3 , they must establish their own blood supply through angiogenesis, and there is substantial evidence that angiogenesis is regulated by platelets. [10][11][12] In malignancy, platelets are the major serum source of many potent proangiogenic proteins, including more than 80% of circulating vascul...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

Battinelli

Markens

Kulenthirarajan

et al. 2014

Blood

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“…Several stimulators of platelet activation have been reported, including ADP and LTC 4 . 37,38 Both P2Y12 and CysLTR1 are involved in the PI3K/Akt pathway, 36,40 which strongly suggests the synergistic effects of the two respective antagonists Clo/Mon. We could not demonstrate the effects of LTC 4 on platelet activation, which were demonstrated previously, 35 possibly due to the prolonged activation of platelets during the induction period in our asthma mouse F I G U R E 7 Correlations between platelet-eosinophil aggregations (PEA) and eosinophil counts with inflammatory mediators and leukotriene E4 (LTE 4 ).…”

Section: Correlation Of Pea and Eosinophil Count With Inflammatory mentioning

confidence: 98%

“…Adenosine diphosphate is known to stimulate platelets thorough a phosphoinositide 3-kinase (PI3K)/Akt-dependent pathway. 37,38 Both P2Y12 and CysLTR1 are involved in the PI3K/Akt pathway, 36,40 which strongly suggests the synergistic effects of the two respective antagonists Clo/Mon. P2Y12R antagonists inhibit eosinophil degranulation.…”

Section: Correlation Of Pea and Eosinophil Count With Inflammatory mentioning

confidence: 98%

The synergistic effects of clopidogrel with montelukast may be beneficial for asthma treatment

Trinh

Nguyen

Choi

et al. 2019

J Cellular Molecular Medi

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Platelets modulate asthma pathogenesis by forming the platelet‐eosinophil aggregation (PEA), which facilitates the activation of eosinophils. Platelets exhibit the purinergic receptor (P2Y12R), which responds to cysteinyl leukotriene E4 (LTE 4 ). We have suggested that the combination of an antiplatelet drug (clopidogrel, [Clo]) and montelukast (Mon) would synergistically suppress asthma. BALB/c mice were intraperitoneally sensitized with ovalbumin (OVA) on days 0 and 14 and subsequently challenged on days 28‐30 and 42‐44. Mice were administered with Clo (10 mg/kg), Mon (10 mg/kg) or both drugs (Clo/Mon) orally 30 minutes before the OVA (1%) challenge on days 42‐44. Mice were assayed for airway hyper‐responsiveness (AHR) to methacholine and airway inflammation. Clopidogrel and montelukast attenuated the increased AHR; the combined treatment was more effective than a single treatment for total and eosinophil counts (all P < 0.05). Levels of interleukin (IL)‐4, IL‐5, IL‐13, platelet factor 4, eosinophil peroxidase and LTE 4 increased in the bronchoalveolar lavage fluid of asthmatic mice, but these levels decreased in mice treated with Clo/Mon (all P < 0.05). Goblet cell hyperplasia decreased in response to Clo/Mon. Mouse platelets and eosinophils were isolated and co‐cultured for an in vitro assay with 10 µmol/L adenosine diphosphate (ADP), LTE 4 (200 nmol/L), Mon (1 µmol/L), Clo (1 µmol/L) and Clo/Mon (1 µmol/L). Flow cytometry revealed that the increased formation of the PEA (%) was fully mediated by ADP and partly mediated by LTE 4 . Clo/Mon reduced ADP‐induced PEA formation and P‐selectin expression ( P < 0.05). In conclusion, Clo/Mon synergistically relieved asthma by inhibiting ADP‐mediated PEA formation.

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“…PAR is a subfamily of the seven-pass transmembrane G-protein-coupled receptors, including PAR1, PAR2, PAR3 and PAR4 ( 25 ). PAR1 is expressed on platelets and is activated by thrombin or tissue factor in the tumor microenvironment ( 26 , 27 ). Notably, PAR1 is also expressed in multiple tumor cells, and inhibition of PAR1 may suppress tumor growth and metastasis ( 28 ).…”

Section: Introductionmentioning

confidence: 99%

Activation of platelet protease-activated receptor-1 induces epithelial-mesenchymal transition and chemotaxis of colon cancer cell line SW620

Jia¹,

Zhang²,

Miao³

et al. 2015

Oncology Reports

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The aim of the present study was to examine the role of protease-activated receptor-1 (PAR1)-stimulated platelet activation in the epithelial-mesenchymal transition (EMT) and migration of colon cancer cells, and to identify the underlying mechanisms. TFLLR-NH2, a PAR1 agonist, was used to activate platelets and the platelet supernatants were used to treat the SW620 colon cancer cell line. Expression of E-cadherin and vimentin on SW620 cells was detected by immunofluorescence and western blotting, and the level of the transforming growth factor β1 (TGF-β1) was measured using ELISA following the activation of platelets by TFLLR-NH2. miR-200b expression was detected using quantitative PCR in SW620 cells. In order to investigate the chemotactic ability of the SW620 cells, the expression of CXC chemokine receptor type 4 (CXCR4) was measured by flow cytometry. Transwell migration assays were performed following exposure of the cells to the supernatant of PAR1-activated platelets. SW620 cells cultured in the supernatant of TFLLR-NH2-activated platelets upregulated E-cadherin expression and downregulated the vimentin expression. In the in vitro platelet culture system, a TFLLR-NH2 dose-dependent increase of secreted TGF-β1 was detected in the supernatant. The activation of PAR1 on the platelets led to the inhibition of miR-200b expression in the SW620 cells that were cultured in platelet-conditioned media. The number of SW620 cells that penetrated through the Transwell membrane increased with the dose of TFLLR-NH2 used to treat the platelets. The percentage of CXCR4-positive SW620 cells was significantly higher when they were exposed to the supernatant of platelets cultured for 24 h with PAR1 agonist than when cultured in non-conditioned media (40.89±6.74 vs. 3.47±1.40%, P<0.01). Platelet activation with a PAR1 agonist triggered TGF-β secretion, which induced EMT of SW620 human colon cancer cells via the downregulation of miR-200b expression, and activated platelets had a chemotactic effect on colon cancer cells mediated by the upregulation of CXCR4 on the cell surface.

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A critical role of thrombin/PAR-1 in ADP-induced platelet secretion and the second wave of aggregation

Cited by 27 publications

References 45 publications

Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

The synergistic effects of clopidogrel with montelukast may be beneficial for asthma treatment

Activation of platelet protease-activated receptor-1 induces epithelial-mesenchymal transition and chemotaxis of colon cancer cell line SW620

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