Tissue Factor encryption and decryption: Facts and controversies

Rao, L. Vijaya Mohan; Kothari, Hema; Pendurthi, Usha R.

doi:10.1016/j.thromres.2012.02.021

Cited by 43 publications

(40 citation statements)

References 58 publications

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“…PDI has been suggested to play a role in tissue factor de-encryption [30]. PDI may facilitate tissue factor deencryption through the formation of the Cys186-Cys209 disulfide bond in the extracellular domain of tissue factor [31,32].…”

Section: Resultsmentioning

confidence: 99%

“…A number of studies have examined the role of phosphatidylserine exposure and PDI activity in tissue factor decryption [28][29][30][31][32]. Although phosphatidylserine levels were significantly increased on HUVEC treated with cisplatin/gemcitabine combination therapy, inhibition of cell surface phosphatidylserine did not attenuate tissue factor activity (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Lung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryption

Lysov

Swystun

Kuruvilla³

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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Lung cancer patients undergoing chemotherapy have an elevated risk for thrombosis. However, the mechanisms by which chemotherapy agents increase the risk for thrombosis remains unclear. The aim of this study was to determine the mechanism(s) by which lung cancer chemotherapy agents cisplatin, carboplatin, gemcitabine, and paclitaxel elicit increased tissue factor activity on endothelial cells, A549 cells, and monocytes. Tissue factor activity, tissue factor antigen, and phosphatidylserine exposure were measured on chemotherapy-treated human umbilical vein endothelial cells (HUVEC), A549 cells, and monocytes. Cell surface protein disulfide isomerase (PDI) and cell surface free thiol levels were measured on HUVEC and A549 non-small cell lung carcinoma cells. Treatment of HUVECs, A549 cells, and monocytes with lung cancer chemotherapy significantly increased cell surface tissue factor activity. However, elevated tissue factor antigen levels were observed only on cisplatin-treated and gemcitabine-treated monocytes. Cell surface levels of phosphatidylserine were increased on HUVEC and monocytes treated with cisplatin/gemcitabine combination therapy. Chemotherapy also resulted in increased cell surface levels of PDI and reduced cell surface free thiol levels. Glutathione treatment and PDI inhibition, but not phosphatidylserine inhibition, attenuated tissue factor activity. Furthermore, increased tissue factor activity was reversed by reducing cysteines with dithiothreitol. These studies are the first to demonstrate that lung cancer chemotherapy agents increase procoagulant activity on endothelial cells and A549 cells by tissue factor decryption through a disulfide bond formation in a PDI-dependent mechanism.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryption

Lysov

Swystun

Kuruvilla³

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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“…The discrepancy between TF antigen expression and activity suggests that MP-associated TF from HEK-293T cells is partially encrypted relative to MP-TF from the EOC cell lines. Reduced phosphatidylserine exposure, inhibition of TF-FVIIa by membrane bound TFPI, or conformational regulation of TF via labile disulfide “switching” may contribute to encryption of TF activity [30, 31]. Disruption of TF regulatory mechanisms in EOC may contribute to an enhanced procoagulant phenotype relative to normal epithelium.…”

Section: Discussionmentioning

confidence: 99%

Tissue factor-factor VIIa complex triggers protease activated receptor 2-dependent growth factor release and migration in ovarian cancer

Chanakira

Westmark

Ong

et al. 2017

Gynecologic Oncology

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Objective Enhanced tissue factor (TF) expression in epithelial ovarian cancer (EOC) is associated with aggressive disease. Our objective was to evaluate the role of the TF-factor VIIa-protease-activated receptor-2 (PAR-2) pathway in human EOC. Methods TCGA RNAseq data from EOC databases were analyzed for PAR expression. Cell and microparticle (MP) associated TF protein expression (Western blot) and MP-associated coagulant activity were determined in human EOC (SKOV-3, OVCAR-3 and CaOV-3) and control cell lines. PAR-1 and PAR-2 protein expression were similarly examined. The PAR dependence of VEGF-A release (ELISA) and chemotactic migration in response to FVIIa and cellular proliferation in response to thrombin was evaluated with small molecule antagonists. Results Relative mRNA expression consistently demonstrated PAR-2>PAR-1≫PAR-3/4 in multiple EOC datasets. Human EOC cell line lysates confirmed expression of TF, PAR-1 and PAR-2 proteins. MPs isolated from EOC cell lines demonstrated markedly enhanced (4–10 fold) TF coagulant activity relative to control cell lines. FVIIa induced a dose-dependent increase in VEGF-A release (2.5-3 fold) from EOC cell lines that was abrogated by the PAR-2 antagonist ENMD-1068. FVIIa treatment of CaOV-3 and OVCAR-3 cells resulted in increased chemotactic migration that was abolished by ENMD-1068. Thrombin induced dose-dependent EOC cell line proliferation was completely reversed by the PAR-1 antagonist vorapaxar. Small molecule antagonists had no effect on these phenotypes without protease present. Conclusions Enhanced activity of the TF-FVIIa-PAR-2 axis may contribute to the EOC progression via PAR-2 dependent signaling that supports an angiogenic and invasive phenotype and local thrombin generation supporting PAR-1 dependent proliferation.

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“…9,11,12 However, molecular differences between cryptic and procoagulant TF and the mechanisms that are responsible for the conversion from one to the other form are poorly understood and often controversial. 11,13 Nonetheless, most of the evidence in the literature suggests that externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane plays a critical role in regulating TF procoagulant activity at the cell surface. 9 However, other pathways, such as the thioredoxin system or thiol-disulfide exchange pathways involving protein-disulfide isomerase (PDI), may also contribute to TF activation by altering TF structure 14–16 or through the modulation of PS exposure.…”

Section: Introductionmentioning

confidence: 99%

Sphingomyelin encrypts tissue factor: ATP-induced activation of A-SMase leads to tissue factor decryption and microvesicle shedding

2017

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A majority of tissue factor (TF) on cell surfaces exists in an encrypted state with minimal to no procoagulant activity. At present, it is unclear whether limited availability of phosphatidylserine (PS) and/or a specific membrane lipid in the outer leaflet of the plasma membrane contributes to TF encryption. Sphingomyelin (SM) is a major phospholipid in the outer leaflet, and SM metabolism is shown to be altered in many disease settings that cause thrombotic disorders. The present study is carried out to investigate the effect of SM metabolism on TF activity and TF+ microvesicles (MVs) release. In vitro studies using TF reconstituted into liposomes containing varying molar ratios of SM showed that a high molar ratio of SM in the proteoliposomes inhibits TF coagulant activity. Treatment of macrophages with sphingomyelinase (SMase) that hydrolyzes SM in the outer leaflet results in increased TF activity at the cell surface and TF+ MVs release without increasing PS externalization. Adenosine triphosphate (ATP) stimulation of macrophages that activates TF and induces MV shedding also leads to translocation of acid-sphingomyelinase (A-SMase) to the plasma membrane. ATP stimulation increases the hydrolysis of SM in the outer leaflet. Inhibition of A-SMase expression or activity not only attenuates ATP-induced SM hydrolysis, but also inhibits ATP-induced TF decryption and TF+ MVs release. Overall, our novel findings show that SM plays a role in maintaining TF in an encrypted state in resting cells and hydrolysis of SM following cell injury removes the inhibitory effect of SM on TF activity, thus leading to TF decryption.

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Tissue Factor encryption and decryption: Facts and controversies

Cited by 43 publications

References 58 publications

Lung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryption

Lung cancer chemotherapy agents increase procoagulant activity via protein disulfide isomerase-dependent tissue factor decryption

Tissue factor-factor VIIa complex triggers protease activated receptor 2-dependent growth factor release and migration in ovarian cancer

Sphingomyelin encrypts tissue factor: ATP-induced activation of A-SMase leads to tissue factor decryption and microvesicle shedding

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