Role of thrombin receptor in breast cancer invasiveness

Henrikson, Katherine P.; Salazar, Sandra; Fenton, John W.; Pentecost, Brian T.

doi:10.1038/sj.bjc.6690063

Cited by 114 publications

(90 citation statements)

References 34 publications

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“…Expression of the thrombin receptor has been detected in human carcinoma cell lines including colon adenocarcinoma (Wojtukiewicz et al, 1995), laryngeal (Kaufmann et al, 1997), breast (EvenRam et al, 1998;Henrikson et al, 1999), pancreatic (Rudroff et al, 1998), and oral squamous cell carcinoma (Liu et al, 2001). We have demonstrated that the metastatic melanoma cells A375SM and WM266-4 overexpress the thrombin receptor (Figure 1).…”

Section: Role Of the Thrombin Receptor In Melanomamentioning

confidence: 87%

“…The thrombin receptor has recently been implicated to play a central role in tumorigenesis and metastasis (Even-Ram et al, 1998;Nierodzik et al, 1998;Henrikson et al, 1999). Expression of the thrombin receptor has been detected in human carcinoma cell lines including colon adenocarcinoma (Wojtukiewicz et al, 1995), laryngeal (Kaufmann et al, 1997), breast (EvenRam et al, 1998;Henrikson et al, 1999), pancreatic (Rudroff et al, 1998), and oral squamous cell carcinoma (Liu et al, 2001).…”

Section: Role Of the Thrombin Receptor In Melanomamentioning

confidence: 99%

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Role and regulation of the thrombin receptor (PAR-1) in human melanoma

2003

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To determine treatment strategies and predict the clinical outcome of patients with melanoma it is important to understand the etiology of this disease. Recently, there has been some insight into molecular basis of melanoma including identification of a few of the regulatory factors and genes involved in this disease. For instance, the transcription factor AP-2 plays a tumor suppressor-like role in melanoma progression by regulating genes involved in tumor growth and metastasis. Previously, we have shown that the progression of human melanoma to the metastatic phenotype is associated with loss of AP-2 expression and deregulation of target genes such as MUC18/MCAM, c-KIT, and MMP-2. Increasing evidence demonstrates that the thrombin receptor (proteaseactivated receptor-1, PAR-1) plays a major role in tumor invasion and contributes to the metastatic phenotype of human melanoma. This review focuses on the role of the thrombin receptor in melanoma and its regulation by AP-2. We show that loss of AP-2 expression in metastatic melanoma cells correlates with overexpression of the thrombin receptor. Our analysis of AP-2/Sp1 complexes within the regulatory region of the thrombin receptor demonstrates that AP-2 binds the proximal 3 0 region of the promoter and diminishes PAR-1 expression. Levels of AP-2 and Sp1 proteins in a panel of melanoma cell lines demonstrated a marked decrease in the ratio of AP-2/ Sp1, a decrease that correlated with overexpression of PAR-1 in metastatic melanoma cells. We propose that loss of AP-2 results in increased expression of the thrombin receptor, which subsequently contributes to the metastatic phenotype of melanoma by upregulating the expression of adhesion molecules, proteases, and angiogenic molecules.

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Section: Role Of the Thrombin Receptor In Melanomamentioning

confidence: 87%

Section: Role Of the Thrombin Receptor In Melanomamentioning

confidence: 99%

Role and regulation of the thrombin receptor (PAR-1) in human melanoma

2003

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“…In the presence of PAR-1 blocking antibodies, the effects of APC were attenuated. To verify that the PAR-1 blocking antibodies were properly blocking the binding of the protease to the receptor, cells were also treated with 5 nM α-IIa, a known ligand of the PAR-1 receptor that will affect migration of the MDA-MB-231 through its activation [37][38][39]. α-IIa alone or α-IIa with control IgG increased chemotaxis approximately 150%, and this increase was attenuated in the presence of the PAR-1 blocking antibodies.…”

Section: Apc Interaction With Par-1 Is Also Necessary To Increase Chementioning

confidence: 99%

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

Beaulieu

Church

2007

Experimental Cell Research

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Activated protein C (APC) is a serine protease that regulates thrombin (IIa) production through inactivation of blood coagulation factors Va and VIIIa. APC also has non-hemostatic functions related to inflammation, proliferation, and apoptosis through various mechanisms. Using two breast cancer cell lines, MDA-MB-231 and MDA-MB-435, we investigated the role of APC in cell chemotaxis and invasion. Treatment of cells with increasing APC concentrations (1-50 μg/ml) increased invasion and chemotaxis in a concentration-dependent manner. Only the active form of APC increased invasion and chemotaxis of the MDA-MB-231 cells when compared to 3 inactive APC derivatives. Using a modified "checkerboard" analysis, APC was shown to only affect migration when plated with the cells; therefore, APC is not a chemoattractant. Blocking antibodies to endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1) attenuated the effects of APC on chemotaxis in the MDA-MB-231 cells. Finally, treatment of the MDA-MB-231 cells with the proliferation inhibitor, Na butyrate, showed that APC did not increase migration by increasing cell number. Therefore, APC increases invasion and chemotaxis of cells by binding to the cell surface and activating specific signaling pathways through EPCR and PAR-1.

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“…7 PAR1 and PAR2 are important in tumor cell motility in melanoma 23,24 and PAR1 is involved in the invasive and metastatic processes of breast, 25,26 ovarian, 6 and pancreatic cancer. 27 PAR1 also has been identified as an oncogene in the transformation of NIH3T3 mouse fibroblasts 28,29 and ectopic expression of PAR1 confers tumorigenicity in PAR1-null breast carcinoma cells.…”

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confidence: 99%

Targeting Protease-Activated Receptor-1 with Cell-Penetrating Pepducins in Lung Cancer

Cisowski

O’Callaghan

Kuliopulos

et al. 2011

The American Journal of Pathology

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Protease-activated receptors (PARs) are G-proteincoupled receptors that are activated by proteolytic cleavage and generation of a tethered ligand. High PAR1 expression has been documented in a variety of invasive cancers of epithelial origin. In the present study, we investigated the contribution of the four PAR family members to motility of lung carcinomas and primary tumor samples from patients. We found that of the four PARs, only PAR1 expression was highly increased in the lung cancer cell lines. Primary lung cancer cells isolated from patient lung tumors migrated at a 10-to 40-fold higher rate than epithelial cells isolated from nonmalignant lung tissue. Cellpenetrating pepducin inhibitors were generated against the first (i1) and third (i3) intracellular loops of PAR1 and tested for their ability to inhibit PAR1-driven migration and extracellular regulated kinase (ERK)1/2 activity. The PAR1 pepducins showed significant inhibition of cell migration in both primary and established cell lines similar to silencing of PAR1 expression with short hairpin RNA (shRNA). Unlike i1 pepducins, the i3 loop pepducins were effective inhibitors of PAR1-mediated ERK activation and tumor growth. Comparable in efficacy with Bevacizumab, monotherapy with the PAR1 i3 loop pepducin P1pal-7 provided significant 75% inhibition of lung tumor growth in nude mice. We identify the PAR1-ERK1/2 pathway as a feasible target for therapy in lung cancer. Lung cancer is the leading cause of cancer deaths in the United States and worldwide, and is the second most common cancer overall. 1 The majority of patients eventually develop distant metastases, which leads to substantial morbidity and mortality. Currently available chemotherapeutic regimens for the treatment of non-small-cell lung cancer (NSCLC) include combinations of cisplatin or carboplatin, and etoposide, paclitaxel, docetaxel, gemcitabine, vinorelbin, and irinotecan. These regimens are generally not curative and may confer modest prolongation of life and symptomatic relief. 2,3 More recently, targeted therapies have become available for the treatment of lung cancer. These include small molecules and antibodies that target epidermal growth factor receptor and vascular endothelial growth factor receptor. However, the currently available molecular therapies still result in relatively modest prolongation of median and overall survival, pointing to the necessity for developing more effective treatment modalities for patients with advanced NSCLC.Emerging evidence has identified protease activated receptor-1 (PAR1) as a promising target to impact tumor progression, metastasis, and angiogenesis in a variety of cancers including breast, ovarian, melanoma, prostate, and colon cancer. 4 -7 However, the role of PAR1 and the other PAR family members in lung cancer is largely unexplored. To date, four different PARs have been identified: PAR1, PAR2, PAR3, and PAR4. 8,9 -13 PAR1 originally was discovered on platelets and serves as the prototype for this specialized class of proteolytically activ...

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Role of thrombin receptor in breast cancer invasiveness

Cited by 114 publications

References 34 publications

Role and regulation of the thrombin receptor (PAR-1) in human melanoma

Role and regulation of the thrombin receptor (PAR-1) in human melanoma

Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

Targeting Protease-Activated Receptor-1 with Cell-Penetrating Pepducins in Lung Cancer

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