Structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis(490 views) Carriero MV, Longanesi-cattani I, Bifulco K, Maglio O, Lista L, Barbieri A, Votta G, Masucci MT, Arra C, Franco R, De Rosa M, Stoppelli MP, Pavone V
Keywords: Antineoplastic Agent, Arginine, Arginylglutamylarginylphenylalaninamide, Cd51 Antigen, Formylmethionylleucylphenylalanine, Formylpeptide Receptor, Green Fluorescent Protein, Matrigel, Plasminogen Activator Inhibitor, Serine, Tyrosine, Unclassified Drug, Urokinase Receptor, Vitronectin Receptor, Animal Cell, Animal Experiment, Animal Model, Animal Tissue, Article, Binding Affinity, Cancer Cell Culture, Cancer Chemotherapy, Cancer Inhibition, Cancer Invasion, Cell Migration, Cell Proliferation, Cell Surface, Concentration Response, Controlled Study, Drug Design, Drug Potency, Drug Protein Binding, Drug Structure, Drug Synthesis, Embryo, Female, Fibrosarcoma, Fluorescence Analysis, Human, Human Cell, In Vivo Study, Internalization, Leukemia Cell, Lung Metastasis, Mast Cell Leukemia, Mouse, Nonhuman, Peptide Synthesis, Priority Journal, Protein Expression, Protein Protein Interaction, Protein Structure, Structure Activity Relation, Tumor Volume, Wound Closure, Wound Healing Impairment, Cell Movement, Immunoprecipitation, Lung Neoplasms, Nude, Microscopy, Molecular, Neoplasm Metastasis, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments, Protein Conformation, Urokinase Plasminogen Activator,
Affiliations: *** IBB - CNR ***
Department of Experimental Oncology, National Cancer Institute of Naples, Via M. Semmola, 80131 Naples, Italy
Department of Human Pathology, National Cancer Institute of Naples, Naples, Italy
Department of Chemistry, University of Naples Federico II, Naples, Italy
IBB-National Research Council, Naples, Italy
Institute of Genetics and Biophysics Adriano Buzzati-Traverso, National Research Council, Naples, Italy
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Perez, D. M., Karnik, S. S., Multiple signaling states of G-protein-coupled receptors (2005) Pharmacol Rev, 57, pp. 147-161
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Structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis
The urokinase-type plasminogen activator receptor (uPAR) plays a central role in sustaining the malignant phenotype and promoting tumor metastasis. The Ser(88)-Arg-Ser-Arg-Tyr 92 is the minimum chemotactic sequence of uPAR required to induce the same intracellular signaling as its ligand uPA. Here, we describe the generation of new peptide inhibitors of cell migration and invasion derived from SRSRY by a drug design approach. Ac-Arg-Glu-Arg-Phe-NH(2) (i.e., RERF), which adopts a turned structure in solution, was selected for its ability to potently prevent SRSRY-directed cell migration. Fluorescein-RERF associates with very high affinity to RBL-2H3 rat basophilic leukemia cells expressing the human formyl peptide receptor (FPR). Accordingly, femtomolar concentrations of RERF prevent agonist-dependent internalization of FPR and inhibit N-formyl-Met-Leu-Phe-dependent migration in a dose-dependent manner. In the absence of FPR, fluorescein-RERF binds to cell surface at picomolar concentrations in an alpha v integrin-dependent manner. The involvement of vitronectin receptor is further supported by the findings that 100 pmol/L RERF selectively inhibits vitronectin-dependent RBL-2H3 cell migration and prevents SRSRY-triggered uPAR/alpha v association. Furthermore, RERF reduces the speed of wound closure and the extent of Matrigel invasion by human fibrosarcoma HT1080 cells without affecting cell proliferation. Finally, a 3- to 5-fold reduction of lung metastasis number and size in nude mice following i.v. injection of green fluorescent protein-expressing HT1080 cells in the presence of 3.32 mg/kg RERF is observed. Our findings indicate that RERF effectively prevents malignant cell invasion in vivo with no signs of toxicity and may represent a promising prototype drug for anticancer therapy. [Mol Cancer Ther 2009;8(9):2708-17]
Structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis
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Structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis
Petraglia F, Singh AA, Carafa V, Nebbioso A, Conte M, Scisciola L, Valente S, Baldi A, Mandoli A, Petrizzi VB, Ingenito C, De Falco S, Cicatiello V, Apicella I, Janssen-megens EM, Kim B, Yi G, Logie C, Heath S, Ruvo M, Wierenga ATJ, Flicek P, Yaspo ML, Della Valle V, Bernard O, Tomassi S, Novellino E, Feoli A, Sbardella G, Gut I, Vellenga E, Stunnenberg HG, Mai A, Martens JHA, Altucci L * Combined HAT/EZH2 modulation leads to cancer-selective cell death(284 views) Oncotarget (ISSN: 1949-2553electronic, 1949-2553linking), 2018 May 22; 9(39): 25630-25646. Impact Factor:5.008 ViewExport to BibTeXExport to EndNote