title: Targeting protease-activated receptor-1 with cell-penetrating pepducins in lung cancer.
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.
authors.affiliation: Division of Hematology/Oncology, Molecular Oncology Research Institute, Tufts Medical Center, Box 7510, 750 Washington St., Boston, MA 02111, USA.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Cisowski
authors.forename: Katie
authors.initials: K
authors.lastname: O'Callaghan
authors.forename: Athan
authors.initials: A
authors.lastname: Kuliopulos
authors.forename: John
authors.initials: J
authors.lastname: Yang
authors.forename: Nga
authors.initials: N
authors.lastname: Nguyen
authors.forename: Qing
authors.initials: Q
authors.lastname: Deng
authors.forename: Eric
authors.initials: E
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Fogel
authors.forename: Sarah
authors.initials: S
authors.lastname: Tressel
authors.forename: Caitlin
authors.initials: C
authors.lastname: Foley
authors.forename: Anika
authors.initials: A
authors.lastname: Agarwal
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Hunt
authors.forename: Tom
authors.initials: T
authors.lastname: McMurry
authors.forename: Larry
authors.initials: L
authors.lastname: Brinckerhoff
authors.forename: Lidija
authors.initials: L
authors.lastname: Covic
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D055666:Lipopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014018:Tissue Distribution; D010975:Platelet Aggregation Inhibitors
chemical_list: D055666:Lipopeptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; D043562:Receptors, G-Protein-Coupled; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010975:Platelet Aggregation Inhibitors