UMLS:C0376358 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombin and trypsin induce cell signaling through a subclass of G-protein-coupled receptors called the protease-activated receptors (PARs). In many cells, PAR signaling results in the activation of RhoA and other members of the Rho family of small GTPases which are involved in cytoskeletal reorganization. The expression of PARs and their role in the activation of Rho GTPases in prostate cancer cells are not clearly known. FACS analysis demonstrated that the androgen-dependent LNCaP cells express PAR1, PAR2, and PAR4 but not PAR3. Stimulation with thrombin and trypsin resulted in the rapid activation of RhoA in a dose-dependent manner with an EC(50) of 1.0 and 5 nM, respectively. Activation of RhoA was enhanced by, but not dependent on, the presence of 1 nM dihydrotestosterone. Inhibition of the proteolytic properties of thrombin by hirudin and trypsin by diisopropyl fluorophosphate abolished the observed RhoA activation. Stimulation with 150 microM PAR-activating peptides TFFLRN (PAR1), SLIGKV (PAR2), and AYPGKF (PAR4) demonstrated that PAR1 and PAR2 mediated protease-activated RhoA signaling. Fluorescent microscopy studies showed that LNCaP cells treated with either thrombin (10 nM) or trypsin (10 nM) developed an increased number of filopodia, stress fibers, and focal adhesions relative to untreated cells. These observations represent the first report of PAR signaling in prostate cancer cells as well as the ability of PAR2 to mediate RhoA activation. Since the activation of RhoA is important for cytoskeletal reorganization, we postulate that PAR-mediated RhoA activation may be a major signaling pathway in the biology of prostate cancer.
...
PMID:Protease-activated receptor mediated RhoA signaling and cytoskeletal reorganization in LNCaP cells. 1253 82

Thrombin generation is increased in men with advanced prostate cancer. Thrombin has the ability to interact with, and affect the biology of, a variety of cell types including prostate cancer cell lines. We therefore looked for correlations between thrombin generation and other markers of disease activity in spot urine samples obtained from men with advanced prostate cancer. Excretion of part of the prothrombin activation peptide F(1+2) (called here iF2), interleukin-6 (IL-6), the bone turnover marker deoxypyridinoline (DpD), and vascular endothelial growth factor (VEGF) were quantitated in spot urine samples collected from 37 men with hormone-refractory prostate cancer. Following log transformation of the data, significant correlations were found by univariate analysis between the excretion of a marker of thrombin generation (iF2) and IL-6, DpD and VEGF, as well as between IL-6 and DpD or VEGF excretion. No correlation was found between any marker and serum PSA level. After multivariate analysis, a significant correlation remained between thrombin generation and IL-6 excretion. Analysis of a second urine specimen obtained from 19 of the subjects 1 to 7 months after the first also revealed a significant correlation between thrombin generation and IL-6, DpD, and VEGF excretion. These data provide evidence of a correlation between thrombin generation/coagulation system activation and IL-6 generation in patients with cancer. They provide a rationale for studying the effects of inhibitors of thrombin generation upon the biology of prostate cancer.
...
PMID:Correlates of thrombin generation in patients with advanced prostate cancer. 1254 Sep 69

Functional protease-activated receptors (PAR) are expressed by a variety of malignant cells. In the present study, RT-PCR assays demonstrated the expression of the thrombin receptor PAR-1 mRNA in human prostate cancer cell lines DU 145, LnCAP, and SV40-immortalized human prostate epithelial cell line PNT1A. In contrast, the additional thrombin receptors PAR-3 and PAR-4 were not detected. PAR-1 protein localized to the cellular surface was detected by flow cytometry in all three cell lines. To demonstrate the functional importance of the PAR-1, the effects of different concentrations of thrombin on cell proliferation kinetics were assessed. The treatment of growth-arrested cells with varying concentrations of thrombin demonstrated dose- and time-dependent effects. At low concentration (<0.5 U/ml), thrombin induced proliferation of all prostate-derived cell lines. Thrombin at higher concentration (1.0 U/ml) initially stimulated PNT1A and LnCAP cells to proliferate (time of thrombin application 24 h and 48 h) followed by inhibited growth when assessed after 72 h of incubation. In contrast, 1.0 U/ml thrombin caused earlier inhibition of DU 145 proliferation starting at 48 h of incubation. Our results suggest that PAR-1 mediates the proliferation-modulating effects of thrombin on prostate cancer cells.
...
PMID:Expression of functional protease-activated receptor 1 in human prostate cancer cell lines. 1288 80

Clinical, laboratory, histopathological, and pharmacological evidence support the notion that the coagulation system, which is activated in most cancer patients, plays an important role in tumor biology. Our laboratory has provided evidence that thrombin activates angiogenesis, a process which is essential in tumor growth and metastasis. This event is independent of fibrin formation. At the cellular level many actions of thrombin can contribute to activation of angiogenesis: (1). Thrombin decreases the ability of endothelial cells to attach to basement membrane proteins. (2). Thrombin greatly potentiates vascular endothelial growth factor- (VEGF-) induced endothelial cell proliferation. This potentiation is accompanied by up-regulation of the expression of VEGF receptors (kinase insert domain-containing receptor [KDR] and fms-like tyrosine kinase [Flt-1]). (3). Thrombin increases the mRNA and protein levels of alpha (v)beta (3) integrin and serves as a ligand to this receptor. Furthermore, thrombin increases the secretion of VEGF and enhances the expression and protein synthesis of matrix metalloprotease-9 and alpha (v)beta (3) integrin in human prostate cancer PC-3 cells. These results could explain the angiogenic and tumor-promoting effect of thrombin and provide the basis for development of thrombin receptor mimetics or antagonists for therapeutic application.
...
PMID:Role of thrombin in angiogenesis and tumor progression. 1503 98

Thrombin and lysophosphatidic acid (LPA) receptors play important roles in vascular biology, development, and cancer. These receptors activate rho via G(12/13) family heterotrimeric G proteins, which are known to directly activate three distinct rho guanine nucleotide exchange factors (rhoGEFs) that contain a regulator of G protein signaling (RGS) domain (RGS-rhoGEFs). However, it is not known which, if any, of these RGS-rhoGEFs (LARG (leukemia-associated rhoGEF), p115rhoGEF, or PDZrhoGEF) plays a role in G protein-coupled receptor-stimulated rho signaling. Using oligonucleotide small interfering RNAs that suppress specific RGS-rhoGEF expression, we show that thrombin receptor stimulation of rho is primarily mediated by LARG in HEK293T and PC-3 prostate cancer cell lines. In contrast, the LPA-stimulated rho response in PC-3 cells is dependent on PDZrhoGEF expression. Suppression of p115rhoGEF had no effect. Thus different rhoGEFs (LARG and PDZrhoGEF) mediate downstream rho signaling by the thrombin and LPA receptors.
...
PMID:Thrombin and lysophosphatidic acid receptors utilize distinct rhoGEFs in prostate cancer cells. 1514 72

For a long time fibrinopeptide A(FPA), fibrinopeptide B(FPB), D-dimer, FM test, serum FDP, and thrombin anti-thrombin complex(TAT) are being used as molecular markers to for sure diagnose hypercoagulable state and thrombus formation. Indeed these molecular markers are very useful for diagnosing thrombus formation, disseminated intravascular coagulation(DIC), and the indicator of treatment of DIC. But these molecular parameters are not enough and difficult for prognosis of the disease or predicting the complication of patients as the most important subject for clinicians. The soluble fibrin monomer-fibrinogen complex (SF) is a complex coupling fibrin monomer and fibrinogen molecules to be formed in the early-activated state of blood coagulation. Thus such a molecular complex is expected to serve as a parameter for the diagnosis of thrombus formation and DIC, in particular its early stage. The aim of the present study is to evaluate a potential usefulness of a newly developed SF test utilizing an SF specific monoclonal antibody (IF-43). We measured SF together with established other parameters in 195 patients with DIC, subclinical DIC/hypercoagulable state, and non-DIC. The diagnosis of DIC was made based on a modified version of the criteria established by the Ministry of Health, Labor and Welfare of Japan. Underlying disease includes leukemia, malignant lymphoma, myelodysplastic syndrome (MDS), multiple injury, giant ovarian tumor, prostatic cancer with multiple bone metastasis, lung cancer, breast cancer with multiple lung and bone metastasis, severe pneumoniae, sepsis, hemophagocytic syndrome (HPS), and rheumatoid arthritis. The SF levels in DIC patients were significantly higher than those in the subclinical DIC/hypercoagulable state, and the non-DIC patients. Receiver operating characteristic (ROC) analysis shows that the specificity and sensitivity of the SF assay appears to be satisfactory. As the level of SF reflects the thrombin generation activity in plasma, it would serve as a strong tool to selectively kick up the state of thrombin generation. These results indicate that the SF could be a specific and reliable parameter for the diagnosis of DIC and contribute to legitimate managements of patients with DIC. The excessive life response to serious clinical insults, such as sepsis, severe pancreatitis, trauma and shock, is called systemic inflammatory response syndrome (SIRS). Once SIRS occurs, people may often die from serious complications such as adult respiratory distress syndrome (ARDS), acute lung injury (ALI), disseminated intravascular coagulation (DIC) and multiple organ failure (MOF). Especially, ALI followed by pneumoniae associated with SIRS could depend on patient's prognosis and life. That is to say, it seems to be urgent for clinicians to make differential diagnosis between Pneumoniae associated with SIRS and Coagulopathy (PASC) and Simple Pneumoniae (SP). Soluble fibrin monomer-fibrinogen complex(SF) is formed in the early-activated state of blood coagulation. Thus such a molecular complex is expected to serve as a parameter for the diagnosis of coagulopathy, in particular its early stage. The aim of the present study is to make differential diagnosis between Pneumoniae associated with SIRS and Coagulopathy (PASC) and Simple Pneumoniae(SP) by using a newly developed SF test utilizing an SF specific monoclonal antibody (IF-43). We measured SF together with established other parameters, hemogram, blood laboratory items in 7 patients with PASC and 17 patients with SP. The diagnosis of Pneumoniae was defined according to the criteria: clinical symptoms abnormal shadow in both Chest X-p and Chest CT, increased level of CRP, number of WBC. The diagnosis of SIRS was based on the criteria established by American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM) Consensus Conference held in August of 1991 in Northbrook, IL (USA). Underlying disease includes leukemias, malignant lymphoma, myelodysplastic syndrome (MDS), multiple myeloma, idiopathic thrombocytopenia purpura(ITP), multiple injury (bone fracture), cerebral hemorrhage, enterocolitis, Appendicitis, lung cancer, larynx cancer, bronchiolitis obliterans organizing pneumonia(BOOP), chronic obstructive pulmonary disease(COPD), sepsis. The SF levels in PASC patients are significantly higher than those in SP patients (p < 0.001). Otherwise, there is no significant difference of the CRP levels between in PASC group and SP group (p < ns). There is no co-relationship between SF level and D-dimer level. Receiver operating characteristic (ROC) analysis shows that the specificity and sensitivity of the SF assay appears to be quite satisfactory. As the level of SF reflects the thrombin generation activity in plasma, it would serve as a strong tool to selectively kick up the state of thrombin generation. These results indicate that the SF could be a specific and reliable parameter for the diagnosis of PASC and contribute to legitimate managements of patients with PASC.
...
PMID:[A novel molecular marker for thrombus formation and life prognosis--clinical usefulness of measurement of soluble fibrin monomer-fibrinogen complex (SF)]. 1516 5

The effects of the pleiotropic serine protease thrombin on tumor cells are commonly thought to be mediated by the thrombin receptor protease-activated receptor 1 (PAR1). We demonstrate here that PAR1 activation has a role in experimental metastasis using the anti-PAR1 antibodies ATAP2 and WEDE15, which block PAR1 cleavage and activation. Thrombin also stimulates chemokinesis of human melanoma cells toward fibroblast conditioned media and soluble matrix proteins. Thrombin-enhanced migration is abolished by anti-PAR1 antibodies, demonstrating that PAR1 cleavage and activation are required. The PAR1-specific agonist peptide TFLLRNPNDK, however, does not stimulate migration, indicating that PAR1 activation is not sufficient. In contrast, a combination of TFLLRNPNDK and the PAR2 agonist peptide SLIGRL mimics the thrombin effect on migration, whereas PAR2 agonist alone has no effect. Agonist peptides for the thrombin receptors PAR3 and PAR4 used alone or with PAR1 agonist also have no effect. Similarly, activation of PAR1 and PAR2 also enhances chemokinesis of prostate cancer cells. Desensitization with PAR2 agonist abolishes thrombin-enhanced cell motility, demonstrating that thrombin acts through PAR2. PAR2 is cleaved by proteases with trypsin-like specificity but not by thrombin. Thrombin enhances migration in the presence of a cleavage-blocking anti-PAR2 antibody, suggesting that thrombin activates PAR2 indirectly and independent of receptor cleavage. Treatment of melanoma cells with trypsin or PAR2 agonist peptide enhances experimental metastasis. Together, these data confirm a role for PAR1 in migration and metastasis and demonstrate an unexpected role for PAR2 in thrombin-dependent tumor cell migration and in metastasis.
...
PMID:Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis. 1528 Apr 47

The efficiency of small interfering RNA (siRNA)-induced gene knockdown is hampered by low transfection efficiency. We established a novel and simple double transfection method using specific siRNA duplexes targeted against human thrombin receptor PAR-1 in DU 145 prostate cancer cells. The initial siRNA transfection of cell suspensions followed by re-transfection of adherent cells on the following day resulted in undetectable PAR-1 mRNA and absent receptor protein. PAR-1 mRNA expression was silenced for up to five days. Functional studies showed that PAR-1 gene silencing in DU 145 cells abolished the modulating effects of thrombin on cell adhesion to the extracellular matrix proteins, fibronectin and laminin, thus demonstrating the essential role of PAR-1 in mediating thrombin effects on DU 145 cell adhesion.
...
PMID:Double transfection improves small interfering RNA-induced thrombin receptor (PAR-1) gene silencing in DU 145 prostate cancer cells. 1552 81

Protease-activated receptor (PAR) 1, PAR3, and PAR4 are considered "thrombin receptors" because thrombin specifically cleaves the extracellular N-termini of the receptor to unmask a new amino acid terminus, which in turn acts as a peptide ligand by binding intramolecularly to the body of the receptor. Among those 3 family members, PAR1 is the predominant thrombin receptor. Although the thrombin-mediated regulation of clot formation has been studied extensively over the past decades, the possible role of thrombin in tumor metastasis via PAR1 has only recently received attention and is briefly discussed herein.
Clin Prostate Cancer 2004 Dec
PMID:Protease-activated receptor 1: a role in prostate cancer metastasis. 1563 62

We have previously reported that protease-activated receptor 1 (PAR1 or thrombin receptor) is over-expressed in metastatic prostate cancer cell lines compared to prostate epithelial cells. In this study, we examined 1,074 prostate biopsies by tissue microarray analysis and demonstrated that PAR1 expression is significantly increased in prostate cancer compared to normal prostate epithelial cells and benign prostatic hyperplasia. We hypothesized that PAR1 activation contributed to prostate cancer cell progression. We demonstrated that stimulation of PAR1 by thrombin or thrombin receptor activating peptide (TRAP6), in androgen-independent DU145 and PC-3 cells resulted in increased DNA binding activity of the NFkappaB p65 subunit. IL-6 and IL-8 levels were also elevated in conditioned media by at least two-fold within 4-6 h of PAR1 activation. This induction of cytokine production was abrogated by pretreatment of cells with the NFkappaB inhibitor caffeic acid phorbol ester. The p38 and ERK1/2 MAPK signaling cascades were also activated by PAR1 stimulation, whereas the SAPK/JNK pathway was unaffected. Inhibition of p38 and ERK1/2 by SB-203589 and PD-098059, respectively, did not abrogate NFkappaB activity, suggesting an independent induction of NFkappaB by PAR1 stimulation. Furthermore, TUNEL assay showed that activation of PAR1 attenuated docetaxel induced apoptosis through the upregulation of the Bcl-2 family protein Bcl-xL. Akt activation was not observed, suggesting that drug resistance induced by PAR1 was independent of PI3K signaling pathway. Because thrombin and PAR1 are over-expressed in prostate cancer patients, targeting the inhibition of their interaction may attenuate NFkappaB signaling transduction resulting in decreased drug resistance and subsequent survival of prostate cancer cells.
...
PMID:PAR1-mediated NFkappaB activation promotes survival of prostate cancer cells through a Bcl-xL-dependent mechanism. 1605 12

<< Previous 1 2 3 4 Next >>