Proinflammatory signaling functions of thrombin in cancer

Ebrahimi, Safieh; Rahmani, Farzad; Behnam-Rassouli, Reihane; Hoseinkhani, Fatemeh; Parizadeh, Mohammad Reza; Keramati, Mohammad Reza; Khazaie, Majid; Avan, Amir; Hassanian, Seyed Mahdi

doi:10.1002/jcp.25753

Cited by 20 publications

(13 citation statements)

References 84 publications

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“…9 PARs are members of the G-protein-coupled receptor family involved in different processes including hemostasis, thrombosis, and inflammation. 13,14 Signaling functions of thrombin regulate the pathogenesis of many inflammatory diseases, such as central nervous system disorders, cancers, 15,16 and of special interest in this review, cardiovascular disease. 11,12 Following PAR activation, the receptor couples to different G-proteins resulting in the activation of several intracellular signaling pathways including mitogenactivated protein kinases (MAPKs), phospholipase C, phosphatidylinositol 3-kinase, protein kinase C (PKC), cyclooxygenase 2, and Rho-activated protein kinases.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 Following PAR activation, the receptor couples to different G-proteins resulting in the activation of several intracellular signaling pathways including mitogenactivated protein kinases (MAPKs), phospholipase C, phosphatidylinositol 3-kinase, protein kinase C (PKC), cyclooxygenase 2, and Rho-activated protein kinases. 13,14 Signaling functions of thrombin regulate the pathogenesis of many inflammatory diseases, such as central nervous system disorders, cancers, 15,16 and of special interest in this review, cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

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Role of thrombin in the pathogenesis of atherosclerosis

Jaberi

Soleimani

Pashirzad

et al. 2018

J of Cellular Biochemistry

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Atherosclerosis is an arterial disease associated with inflammation. Thrombin is a procoagulant and proinflammatory serine protease that contributes to the pathology of atherosclerosis by enhancing the expression of cell adhesion molecules, inducing the secretion of proinflammatory cytokines, activating inflammatory responses in atherosclerotic plaques, stimulating proliferation of aortic smooth muscle cells, and exacerbating vascular lesions at sites of injury. Hence, thrombin appears to be an important target for treatment of atherosclerosis and thrombin pharmacological inhibitors have significant therapeutic potency for suppressing inflammatory responses in cardiovascular diseases. This review summarizes the proinflammatory signaling functions of thrombin as well as the therapeutic potency of thrombin inhibitors in the pathogenesis of atherosclerosis and hence their potential therapeutic value in this condition.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of thrombin in the pathogenesis of atherosclerosis

Jaberi

Soleimani

Pashirzad

et al. 2018

J of Cellular Biochemistry

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“…As a key initiator of tumorderived hypercoagulopathy, TF is aberrantly expressed in many types of aggressive tumors and may be highly relevant for understanding the disease mechanism and treatment outcome. The importance of TF is also supported by more recent findings with thrombin, a critical TF-cascade protease that impacts tumor progression and cancer immune evasion (34,35).…”

Section: Discussionmentioning

confidence: 72%

mTOR Promotes Tissue Factor Expression and Activity in EGFR-Mutant Cancer

Cong

Zhang

et al. 2020

Front. Oncol.

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Mechanistic target of rapamycin (mTOR) signaling pathway mediates the function of oncogenic receptor tyrosine kinases (RTKs). We aimed to elucidate new role of mTOR in EGFR-mutant (EGFR-mut) non-small cell lung cancer (NSCLC) and glioblastoma (GBM) with a focus on tumor microenvironments. Here, we report a novel regulatory link between mTOR complexes (mTORCs) and tissue factor (TF), an initiator of tumorderived thrombosis. TF is elevated in EGFR-mut NSCLC/GBM cell lines and tumors from patients with poor prognosis. Application of mTORC1/2 inhibitors (AZD8055, WYE-125132, MTI-31, and rapamycin) or genetic mTORC-depletion all reduced TF expression, which appeared to be differentially mediated depending on cellular context. In U87MG and HCC827 cells, mTORC1 exerted a dominant role via promoting TF mRNA transcription. In EGFR-TKI-resistant H1975 and PC9 cells, it was mTORC2 that played a major role in specific repression of lysosomal-targeted TF protein degradation. Successful inhibition of TF expression was demonstrated in AZD8055-or MTI-31treated H1975 and U87MG tumors in mice, while a TF-targeted antibody antagonized TF activity without reducing TF protein. Both the mTOR-and TF-targeted therapy induced a multifaceted remodeling of tumor microenvironment reflecting not only a diminished hypercoagulopathy state (fibrin level) but also a reduced stromal fibrosis (collagen distribution), compromised vessel density and/or maturity (CD31 and/or α-SMA) as well as a substantially decreased infiltration of immune-suppressive M2-type tumor-associated macrophages (CD206/F4/80 ratio). Thus, our results have identified TF as a functional biomarker of mTOR. Downregulation of mTOR-TF axis activity likely contributes to the therapeutic mechanism of mTORC1/2-and TF-targeted agents in EGFR-mut advanced NSCLC and GBM.

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“…Furthermore, disruption of the ATBR prevents the inactivation of the major coagulation enzymes Factor Xa and thrombin by heparin-antithrombin complexes. However, these enzymes may also contribute to additional anticoagulation-independent effects such as by activating protease-activated receptors on cell surfaces or regulating the activity of other proteins through proteolytic cleavage, among other effects [45]. Thus, these nonanticoagulant effects may not be fully evaluated by gsHep.…”

Section: Discussionmentioning

confidence: 99%

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia†

Wat

Hawrylyshyn

Baczyk

et al. 2018

Biology of Reproduction

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Low molecular weight heparin (LMWH) is being investigated as a potential preventative therapy against preeclampsia. There is evidence suggesting that LMWH may prevent preeclampsia through anticoagulation-independent mechanisms. In this study, we compared the in vitro placental, endothelial, and anti-inflammatory effects of a LMWH (dalteparin) with a non-anticoagulant, glycol-split heparin derivative (gsHep). In contrast with dalteparin, gsHep did not interact with antithrombin III, possess significant anti-Factor Xa activity, or significantly prolong in vitro plasma clotting time. However, dalteparin and gsHep were otherwise mechanistically similar, both interacting with soluble fms-like tyrosine kinase-1 (sFlt1) and promoting secretion of the pro-angiogenic protein placental growth factor, but not the anti-angiogenic sFlt1, from healthy placental villous explants. Placental explant media pre-treated with dalteparin or gsHep significantly stimulated endothelial cell tube formation compared to untreated explants. Lastly, dalteparin and gsHep both significantly suppressed inflammation by inhibiting complement activation and leukocyte adhesion to endothelial cells that were activated using serum from preeclamptic women. Our data suggest that non-anticoagulant heparin derivatives may be utilized as a tool to distinguish the anticoagulationindependent mechanisms of LMWH, and provide insight into the role of anticoagulation in the prevention of preeclampsia.

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Proinflammatory signaling functions of thrombin in cancer

Cited by 20 publications

References 84 publications

Role of thrombin in the pathogenesis of atherosclerosis

Role of thrombin in the pathogenesis of atherosclerosis

mTOR Promotes Tissue Factor Expression and Activity in EGFR-Mutant Cancer

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia†

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