Prognostic Role of Protease-Activated Receptors 1 and 4 in Resected Stage IB Non-Small-Cell Lung Cancer

Ghio, P; Cappia, Susanna; Selvaggi, Giovanni; Novello, S.; Lausi, Paolo Olivo; Zecchina, Gabriella; Papotti, M; Borasio, P.; Scagliotti, Giorgio V.

doi:10.3816/clc.2006.n.023

Cited by 28 publications

(29 citation statements)

References 28 publications

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“…30 We determined surface expression of all four PAR members in seven different National Cancer Institute (NCI)-lung cancer cell lines that consisted of five adenocarcinomas, a squamous-cell carcinoma, and a large cell carcinoma using flow cytometry. Of the four PAR family members, PAR1 expression was increased threefold to ninefold in the majority of the lung carcinomas, with maximum expression detected in the adenocarcinomas.…”

Section: Par1 Expression Is Increased In Highly Aggressive Lung Cancementioning

confidence: 99%

“…30 To define the relative importance of PAR1 in lung tumor progression we used in vivo mouse models. Furthermore, because we identified that blockade of PAR1 signaling with i3 pepducins blocks multiple signaling pathways including calcium signaling and the ERK1/2 pathway, whereas i1 pepducin inhibits only migration and partially inhibits calcium, it was of interest to compare the in vivo efficacy of these pepducins.…”

Section: The Par1 I3 Pepducin Inhibits Tumor Growth Of Lung Carcinomamentioning

confidence: 99%

“…Moreover, there was a trend toward shorter 3-year survival in PAR1-positive lung cancers. 30 In the present study, we identified PAR1 as a potential therapeutic target in lung cancer by using cell-penetrating pepducins generated from the first (i1) intracellular and third (i3) intracellular loops of PAR1.…”

mentioning

confidence: 95%

“…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. 4 Recent work by Ghio et al 30 measured PAR1, PAR4, and vascular endothelial growth factor (VEGF) expression in 60 NSCLCs that consisted of 30 adenocarcinomas and 30 squamous cell carcinomas. They found that the majority of lung tumors expressed VEGF and that there was a significant correlation between PAR1 and/or PAR4 expression with VEGF.…”

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confidence: 99%

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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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Section: Par1 Expression Is Increased In Highly Aggressive Lung Cancementioning

confidence: 99%

Section: The Par1 I3 Pepducin Inhibits Tumor Growth Of Lung Carcinomamentioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

See 2 more Smart Citations

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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“…However, numerous studies have shown that PAR1 is overexpressed in invasive and metastatic tumors and that its expression levels directly correlate with the degree of invasiveness of the cancer [20][21][22][23][24][25][26][27][28]. Based on these facts, this receptor is starting to be also considered a promising target for cancer therapy [15], particularly in the search of angiogenesis inhibitors [29].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

Ventosa-Andrés

Valdivielso

Pappos

et al. 2012

European Journal of Medicinal Chemistry

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By applying a diversity oriented synthesis strategy for the search of new antagonists of the thrombin receptor PAR1, a series of peptide-based ureas and thioureas, including analogues of the PAR1 reference antagonist RWJ-58259, has been designed and synthesized. The general synthetic scheme involves reduction of basic amino acid-derived amino nitriles by hydrogen transfer from hydrazine monohydrate in the presence of Raney Ni, followed by reaction with diverse isocyanates and isothiocyanates, and protecting group removal. All new compounds have been evaluated as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN. Some protected peptide-based ureas displayed significant antagonist activity.

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Aberrant expression of proteinase‐activated receptor 4 promotes colon cancer cell proliferation through a persistent signaling that involves Src and ErbB‐2 kinase

Gratio

Walker

Lehy

et al. 2009

Intl Journal of Cancer

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Thrombin is now recognized as an important factor in many cancers. Here, we examined the expression and role of the recently discovered thrombin receptor PAR4, in human colon cancer cells. PAR4 mRNA was found in 10 out of 14 (71%) human colon cancer cell lines tested but not in epithelial cells isolated from normal human colon. This finding is in line with immunostaining results of PAR4 in human colon tumors and its absence in normal human colonic mucosa. Investigation of the functional significance of the aberrant expression of PAR4 in colon cancer cells revealed (i) a prompt increase in intracellular calcium concentration on challenge with PAR4-specific agonist AP4 (100 lM) and (ii) marked mitogenic response (2.5-fold increase in cell number) in a dose-dependent manner on treatment with AP4 (0.1-300 lM). Analysis of the signaling pathways downstream of PAR4 activation in HT29 cells showed (i) a sustained phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2) and (ii) the involvement of epidermal growth factor receptor B-2 (ErbB-2) but not of epidermal growth factor receptor in PAR4-induced mitogen-activated protein kinase activation. Tyrphostin AG1478, the ErbB inhibitor, reversed the action of AP4 on ERK1/2 and ErbB-2 phosphorylation and HT29 cell growth. Finally, the Src inhibitor PP2 abrogated ErbB-2 and ERK phosphorylation and HT29 cell proliferation, suggesting the essential role of Src activity in PAR4-induced phosphorylation of ErbB-2. These data highlight the role of PAR4 as a new important player in the control of colon tumors and underline the critical role of ErbB-2 transactivation. ' 2008 Wiley-Liss, Inc.Key words: colon cancer; thrombin; protease; receptor /PAR4; signal transduction; proliferation; ErbB-2; EGFR The progression from normal colonic mucosa to malignant tumor is a multistep process whereby genetic alterations in prooncogenes and/or tumor suppressor genes can lead to aberrant growth. 1,2 Proteases have long been associated with colon cancer progression because of their ability to degrade extracellular matrices, which facilitates invasion and metastasis. 3 However, recent studies have shown that these enzymes target diverse substrates and favor all steps of tumor evolution. 4 Recently, the traditional view of the role of proteases in tumor growth and progression has significantly changed. Besides their contribution to cancer progression by degrading extracellular matrix proteins, it is now clear that a subclass of proteases serve as signal molecules controlling cell functions through specific membrane receptors, the proteaseactivated receptors (PARs). 5,6 This new class of receptors belongs to the superfamily of the serpentine G protein-coupled receptors (GPCRs). The PARs are activated by low subnanomolar concentrations of serine proteases that cleave a single peptide bond in the N-terminal extracellular domain of the receptor. The resulting new N-terminal domain serves as a receptor agonist. 5,6 This intramolecular ligand binds to the core of the receptor and initiates sig...

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Prognostic Role of Protease-Activated Receptors 1 and 4 in Resected Stage IB Non-Small-Cell Lung Cancer

Cited by 28 publications

References 28 publications

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

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

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

Aberrant expression of proteinase‐activated receptor 4 promotes colon cancer cell proliferation through a persistent signaling that involves Src and ErbB‐2 kinase

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