title: Discovery of PTPRJ agonist peptides that effectively inhibit in vitro cancer cell proliferation and tube formation.
abstract: PTPRJ is a receptor protein tyrosine phosphatase involved in both physiological and oncogenic pathways. We previously reported that its expression is strongly reduced in the majority of explored cancer cell lines and tumor samples; moreover, its restoration blocks in vitro cancer cell proliferation and in vivo tumor formation. By means of a phage display library screening, we recently identified two peptides able to bind and activate PTPRJ, resulting in cell growth inhibition and apoptosis of both cancer and endothelial cells. Here, on a previously discovered PTPRJ agonist peptide, PTPRJ-pep19, we synthesized and assayed a panel of nonapeptide analogues with the aim to identify specific amino acid residues responsible for peptide activity. These second-generation nonapeptides were tested on both cancer and primary endothelial cells (HeLa and HUVEC, respectively); interestingly, one of them (PTPRJ-19.4) was able to both dramatically reduce cell proliferation and effectively trigger apoptosis of both HeLa and HUVECs compared to its first-generation counterpart. Moreover, PTPRJ-pep19.4 significantly inhibited in vitro tube formation on Matrigel. Intriguingly, while ERK1/2 phosphorylation and cell proliferation were both inhibited by PTPRJ-pep19.4 in breast cancer cells (MCF-7 and SKBr3), no effects were observed on primary normal human mammary endothelial cells (HMEC). We further characterized these peptides by molecular modeling and NMR experiments reporting, for the most active peptide, the possibility of self-aggregation states and highlighting new hints of structure-activity relationship. Thus, our results indicate that this nonapeptide might represent a great potential lead for the development of novel targeted anticancer drugs.
authors.affiliation: Dipartimento di Scienze della Salute and ‡Dipartimento di Medicina Sperimentale e Clinica, Università "Magna Græcia" di Catanzaro, Campus "S. Venuta", 88100 Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Francesco
authors.initials: F
authors.lastname: Paduano
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Isabel
authors.initials: I
authors.lastname: Gomez-Monterrey
authors.forename: Anna
authors.initials: A
authors.lastname: Bilotta
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Marina
authors.initials: M
authors.lastname: Sala
authors.forename: Anna
authors.initials: A
authors.lastname: Artese
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Vernieri
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dattilo
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Iuliano
authors.forename: Diego
authors.initials: D
authors.lastname: Brancaccio
authors.forename: Alessia
authors.initials: A
authors.lastname: Bertamino
authors.forename: Simona
authors.initials: S
authors.lastname: Musella
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Nicola
authors.initials: N
authors.lastname: Perrotti
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009010:Monte Carlo Method; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017510:Protein Folding / Q000187:drug effects; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D010455:Peptides; C000592895:cysteinyl-histidyl-histidyl-alanyl-leucyl-threonyl-histidyl-alanyl-cysteine; C486288:PTPRJ protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3