Proteinase-activated receptor 1- and 4-promoted migration of Hep3B hepatocellular carcinoma cells depends on ROS formation and RTK transactivation

Mussbach, Franziska; Henklein, Petra; Westermann, Martin; Settmacher, Utz; Böhmer, Frank‐D.; Kaufmann, Roland

doi:10.1007/s00432-014-1863-4

Cited by 20 publications

(13 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, in platelets, thrombin exerted its effect via a PAR4-dependent mechanism, while our results support a PAR1-dependent mechanism in RBMVEC. On the other hand, in hepatocellular carcinoma cells, thrombin induced ROS via both PAR1 and PAR4 (Mussbach et al, 2015). In endothelial cells from a mouse model of Alzheimer’s disease, a direct thrombin inhibitor blocked ROS generation induced by hypoxia (Tripathy et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of modulation of brain microvascular endothelial cells function by thrombin

et al. 2017

View full text Add to dashboard Cite

Brain microvascular endothelial cells are a critical component of the blood-brain barrier. They form a tight monolayer which is essential for maintaining the brain homeostasis. Blood-derived proteases such as thrombin may enter the brain during pathological conditions like trauma, stroke, and inflammation and further disrupts the permeability of the blood-brain barrier, via incompletely characterized mechanisms. We examined the underlying mechanisms evoked by thrombin in rat brain microvascular endothelial cells (RBMVEC). Our results indicate that thrombin, acting on protease-activated receptor 1 (PAR1) increases cytosolic Ca2+ concentration in RBMVEC via Ca2+ release from endoplasmic reticulum through inositol 1,4,5-trisphosphate receptors and Ca2+ influx from extracellular space. Thrombin increases nitric oxide production; the effect is abolished by inhibition of the nitric oxide synthase or by antagonism of PAR1 receptors. In addition, thrombin increases mitochondrial and cytosolic reactive oxygen species production via PAR1-dependent mechanisms. Immunocytochemistry studies indicate that thrombin increases F-actin stress fibers, and disrupts the tight junctions. Thrombin increased the RBMVEC permeability assessed by a fluorescent flux assay. Taken together, our results indicate multiple mechanisms by which thrombin modulates the function of RBMVEC and may contribute to the blood-brain barrier dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanisms of modulation of brain microvascular endothelial cells function by thrombin

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In numerous cancers, the response to thrombin-induced PAR-1 activation increases cell proliferation, as well as motility and migration in Matrigel barrier assays [ 45 , 46 , 50 , 77 ]. In Hep3B liver carcinoma cells, PAR-1 and PAR-4 activate common promigratory signaling pathways via activation of the receptor tyrosine kinases Met, PDGFR, and ROS kinase, as well as the inactivation of the protein tyrosine phosphatase, PTP1B [ 162 ]. In nasopharyngeal cancer, thrombin-induced PAR-1 activation leads to increased expression of MMP-2 and MMP-9, which are closely associated with tumor metastasis as they can degrade the extracellular matrix and disrupt the basement membrane [ 43 , 60 ].…”

Section: Pars and Proteases—cooperation In Cancer Progressionmentioning

confidence: 99%

Protease-activated receptors (PARs)—biology and role in cancer invasion and metastasis

Wojtukiewicz

Hempel

Sierko

et al. 2015

Cancer Metastasis Rev

120

124

View full text Add to dashboard Cite

Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs—mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well.

show abstract

“…Since TF/FVIIa is known to be able to activate PAR 2 , this ability of TF/FVIIa to activate the PDGFR-β may be due initially to PAR 2 activation. Further evidence for this PAR 2 -PDGFR crosstalk comes from the observation that the PAR 2 -selective agonist peptide, 2-furoyl-LIGRLO-NH 2 , induces phosphorylation and activation of the PDGFR in liver carcinoma cells [53]. Since the PAR 1 -selective agonist peptide, TFLLRN-NH 2 , and the PAR 4 -selective agonist peptide, AYPGKV-NH 2 , can also induce activation of the PDGFR in Hep3B liver carcinoma cells, a coordinated receptor tyrosine kinase signalling of the PARs 1, 2 and 4 in liver carcinoma cells may be suggested [53].…”

Section: Selected Examples Of Par-stimulated Receptor Transactivationmentioning

confidence: 99%

“…In liver carcinoma cells, PAR 2 triggers transactivation of the tyrosine kinase receptor, Met, to promote cell migration and invasion [54,55] and exhibits signalling crosstalk with the PDGFR to induce phosphorylation and activation of the PDGFR [53]. This result suggests that the combined use of a PAR 2 antagonist together with inhibitors for Met or the PDGFR will prove of value in the anti-metastatic therapy of hepatocellular carcinoma.…”

Section: Proteinase-activated Receptor Signalling Receptor Dimerizatmentioning

confidence: 99%

Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

et al. 2013

Self Cite

View full text Add to dashboard Cite

Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR1, PAR2, PAR3 and PAR4, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression. PARs are characterized by a unique activation mechanism involving receptor cleavage by different proteinases at specific sites within the extracellular amino-terminus and the exposure of amino-terminal “tethered ligand“ domains that bind to and activate the cleaved receptors. After activation, the PAR family members are able to stimulate complex intracellular signalling networks via classical G protein-mediated pathways and beta-arrestin signalling. In addition, different receptor crosstalk mechanisms critically contribute to a high diversity of PAR signal transduction and receptor-trafficking processes that result in multiple physiological effects.In this review, we summarize current information about PAR-initiated physical and functional receptor interactions and their physiological and pathological roles. We focus especially on PAR homo- and heterodimerization, transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), communication with other GPCRs, toll-like receptors and NOD-like receptors, ion channel receptors, and on PAR association with cargo receptors. In addition, we discuss the suitability of these receptor interaction mechanisms as targets for modulating PAR signalling in disease.

show abstract

Proteinase-activated receptor 1- and 4-promoted migration of Hep3B hepatocellular carcinoma cells depends on ROS formation and RTK transactivation

Cited by 20 publications

References 64 publications

Mechanisms of modulation of brain microvascular endothelial cells function by thrombin

Mechanisms of modulation of brain microvascular endothelial cells function by thrombin

Protease-activated receptors (PARs)—biology and role in cancer invasion and metastasis

Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

Contact Info

Product

Resources

About