Protease-Activated Receptor 1 (PAR-1) Is Required and Rate-Limiting for Thrombin-Enhanced Experimental Pulmonary Metastasis

Nierodzik, Mary Lynn; Chen, Kui; Takeshita, Kenichi; Li, Jianjun; Huang, Yao-Qi; Feng, Xuesheng; D’Andrea, Michael R.; Andrade‐Gordon, Patricia; Karpatkin, Simon

doi:10.1182/blood.v92.10.3694

Cited by 173 publications

(71 citation statements)

References 28 publications

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“…In support of this observation, thrombin and PAR 1 AP promote the invasion of a highly aggressive breast cancer cell line expressing PAR 1 in an in vitro assay (122). Exposure of certain tumor cells to thrombin and PAR 1 AP also enhances their adhesion to platelets, fibronectin, and von Willebrand factor in vitro and promotes pulmonary metastasis when cells are administered to mice in vivo (209,210). Moreover, overexpression of PAR 1 in certain tumor cells can enhance their metastatic potential in animal models.…”

Section: Cancermentioning

confidence: 87%

Protease-Activated Receptors: Contribution to Physiology and Disease

Ossovskaya

Bunnett

2004

Physiological Reviews

993

1,103

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Proteases acting at the surface of cells generate and destroy receptor agonists and activate and inactivate receptors, thereby making a vitally important contribution to signal transduction. Certain serine proteases that derive from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast cell and neutrophil proteases), and from multiple other sources (e.g., epithelial cells, neurons, bacteria, fungi) can cleave protease-activated receptors (PARs), a family of four G protein-coupled receptors. Cleavage within the extracellular amino terminus exposes a tethered ligand domain, which binds to and activates the receptors to initiate multiple signaling cascades. Despite this irreversible mechanism of activation, signaling by PARs is efficiently terminated by receptor desensitization (receptor phosphorylation and uncoupling from G proteins) and downregulation (receptor degradation by cell-surface and lysosomal proteases). Protease signaling in tissues depends on the generation and release of proteases, availability of cofactors, presence of protease inhibitors, and activation and inactivation of PARs. Many proteases that activate PARs are produced during tissue damage, and PARs make important contributions to tissue responses to injury, including hemostasis, repair, cell survival, inflammation, and pain. Drugs that mimic or interfere with these processes are attractive therapies: selective agonists of PARs may facilitate healing, repair, and protection, whereas protease inhibitors and PAR antagonists can impede exacerbated inflammation and pain. Major future challenges will be to understand the role of proteases and PARs in physiological control mechanisms and human diseases and to develop selective agonists and antagonists that can be used to probe function and treat disease.

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Section: Cancermentioning

confidence: 87%

Protease-Activated Receptors: Contribution to Physiology and Disease

Ossovskaya

Bunnett

2004

Physiological Reviews

993

1,103

View full text Add to dashboard Cite

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“…It is now recognized that the PARs, activated by thrombin, may play a key role in the oncogenic process (Fischer et al, 1995; Even‐Ram et al, 1998, 2001; Nierodzik et al, 1998; Bromberg et al, 2001; Kamath et al, 2001; Chay et al, 2002; Darmoul et al, 2003; Tellez and Bar‐Eli, 2003; Yin et al, 2003; Shi et al, 2004; Bergmann et al, 2006). Since the HCC cells express PAR 3 as well as PARs 1 and 4, the sensitivity of the cells to thrombin activation would be enhanced (Nakanishi‐Matsui et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Thrombin‐mediated hepatocellular carcinoma cell migration: Cooperative action via proteinase‐activated receptors 1 and 4

Kaufmann

Rahn

Pollrich

et al. 2007

Journal Cellular Physiology

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Proteinase-activated receptor-1 (PAR(1)), a thrombin receptor and the prototype of a newly discovered G-protein-coupled receptor subfamily, plays an important role in tumor development and progression. In this study, we documented the expression of the thrombin receptors PAR(1), PAR(3), and PAR(4) in permanent hepatocellular carcinoma (HCC) cell lines and primary HCC cell cultures. Stimulation of HCC cells with thrombin and the PAR(1)-selective activating peptide, TFLLRN-NH(2), increased transmembrane migration across a collagen barrier. This effect was blocked by the PAR(1) antagonist SCH 79797, confirming that the PAR(1) thrombin receptor subtype is involved in regulating hepatoma cell migration. In addition, the PAR(4)-selective agonist, AYPGKF-NH(2), also stimulated HCC cell migration whilst the PAR(4) antagonist, trans-cinnamoyl-YPGKF-NH(2), attenuated the effect of thrombin on HCC cell migration. PAR(1)- and PAR(4)-triggered HCC cell migration was blocked by inhibiting a number of key mediators of signal transduction, including G proteins of the G(i)/G(o) family, matrix metalloproteinases, ERK/MAPKinase, cyclic AMP-dependent protein kinase, Src tyrosine kinase, and the EGF receptor kinase. Our data point to a cooperative PAR(1)/PAR(4) signaling network that contributes to thrombin-mediated tumor cell migration. We suggest that a combined inhibition of coagulation cascade serine proteinases, the two PARs and their complex signaling pathways may provide a new strategy for treating hepatocellular carcinoma.

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“…Pretreatment of tumor cells with thrombin or PAR1 agonist peptides changes their adhesive behavior and increases pulmonary metastasis. 34 Thrombin influences several tumor cell pathways. Thrombin-dependent PAR1 signaling induces proliferation of metastatic tumor cells 35 and can be antiapoptotic.…”

Section: Thrombin Pathways In Metastasismentioning

confidence: 99%

Thrombin Generation and the Pathogenesis of Cancer

Ruf

Mueller²

2006

Semin Thromb Hemost

160

121

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Advanced cancer is associated with a hypercoagulable state that is triggered by tissue factor (TF). TF-initiated thrombin generation is crucial for metastasis through fibrin and platelet deposition, as well as thrombin-dependent protease-activated receptor (PAR) 1 signaling. Surprisingly, PAR2, which is not cleaved by thrombin, appears to cosignal with PAR1 to elicit thrombin effects in metastatic tumor cells. In contrast to TF-driven thrombin pathways in metastasis, direct TF signaling plays a role in angiogenesis-dependent tumor growth. In TF cytoplasmic-domain-deleted mice, PAR2-dependent angiogenesis and tumor growth is enhanced, demonstrating a role for host cell TF signaling. In tumor cells, TF-factor VIIa (FVIIa) activates PAR2 and thereby regulates proangiogenic growth factor expression as well as integrins involving crosstalk with the TF cytoplasmic domain. In addition to thrombin-PAR signaling in metastasis and TF-FVIIa-PAR2 signaling in tumor growth, it is likely that additional protease pathways will prove to be crucial activators of PARs in cancer. Transmembrane serine proteases as well as matrix metalloproteinase are prime candidates for accessory pathways to regulate metastasis, tumor expansion, and angiogenesis dependent on specific features of the local tumor microenvironment.

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Protease-Activated Receptor 1 (PAR-1) Is Required and Rate-Limiting for Thrombin-Enhanced Experimental Pulmonary Metastasis

Cited by 173 publications

References 28 publications

Protease-Activated Receptors: Contribution to Physiology and Disease

Protease-Activated Receptors: Contribution to Physiology and Disease

Thrombin‐mediated hepatocellular carcinoma cell migration: Cooperative action via proteinase‐activated receptors 1 and 4

Thrombin Generation and the Pathogenesis of Cancer

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