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Targeting protease-activated receptor-1 with cell-penetrating pepducins in lung cancer
Jaroslaw Cisowski1, Katie O'Callaghan, Athan Kuliopulos
1Division of Hematology/Oncology, Molecular Oncology Research Institute, Tufts Medical Center, Box 7510, 750 Washington St., Boston, MA 02111, USA.
Abstract:
Protease-activated receptors (PARs) are G-protein-coupled 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. Cell-penetrating 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.
Insights
Protease-activated receptor 1 (PAR1) drives lung cancer cell migration. Inhibiting PAR1 with pepducins significantly reduces tumor growth, identifying the PAR1-ERK pathway as a promising lung cancer therapy target.
Area of Science:
- Oncology
- Molecular Biology
- G-protein coupled receptor signaling
Background:
- Protease-activated receptors (PARs) are implicated in various invasive cancers.
- PAR1, a specific PAR family member, shows high expression in epithelial cancers.
- Lung carcinoma cells exhibit increased motility compared to normal lung epithelial cells.
Purpose of the Study:
- To investigate the role of the four PAR family members in lung carcinoma cell motility.
- To evaluate the efficacy of PAR1-targeting pepducin inhibitors in preclinical lung cancer models.
Main Methods:
- Analysis of PAR family member expression in lung cancer cell lines and primary tumors.
- Assessment of cell migration rates in primary lung cancer cells versus normal lung epithelial cells.
- Generation and testing of PAR1 pepducin inhibitors targeting intracellular loops (i1 and i3) for inhibition of cell migration and ERK1/2 activity.
- Comparison of PAR1 pepducin efficacy with short hairpin RNA (shRNA) silencing and Bevacizumab.
Main Results:
- PAR1 expression was significantly elevated in lung cancer cell lines.
- Primary lung cancer cells demonstrated markedly higher migration rates than nonmalignant cells.
- PAR1 pepducins, particularly i3 loop inhibitors, effectively inhibited PAR1-driven cell migration and ERK activation.
- Monotherapy with P1pal-7 (a PAR1 i3 loop pepducin) achieved 75% lung tumor growth inhibition in mice, comparable to Bevacizumab.
Conclusions:
- The PAR1-ERK1/2 pathway is crucial for lung carcinoma cell motility and growth.
- PAR1 pepducins represent a viable therapeutic strategy for lung cancer.
- Targeting PAR1 offers a promising new avenue for lung cancer treatment.
