title: PIVL, a new serine protease inhibitor from Macrovipera lebetina transmediterranea venom, impairs motility of human glioblastoma cells.
abstract: A novel Kunitz-type serine proteinase inhibitor, termed PIVL, was purified to homogeneity from the venom of the Tunisian snake Macrovipera lebetina transmediterranea. It is a monomeric polypeptide chain cross-linked by three disulfide linkages with an isotope-averaged molecular mass of 7691.7 Da. The 67-residue full-length PIVL sequence was deduced from a venom gland cDNA clone. Structurally, PIVL is built by a single Kunitz/BPTI-like domain. Functionally, it is able to specifically inhibit trypsin activity. Interestingly, PIVL exhibits an anti-tumor effect and displays integrin inhibitory activity without being cytotoxic. Here we show that PIVL is able to dose-dependently inhibit the adhesion, migration and invasion of human glioblastoma U87 cells. Our results also show that PIVL impairs the function of αvβ3 and to a lesser extent, the activity of αvβ6, αvβ5, α1β1 and α5β1 integrins. Interestingly, we demonstrate that the (41)RGN(43) motif of PIVL is likely responsible for its anti-cancer effect. By using time lapse videomicroscopy, we found that PIVL significantly reduced U87 cells motility and affected cell directionality persistence by 68%. These findings reveal novel pharmacological effects for a Kunitz-type serine proteinase inhibitor.
authors.affiliation: Laboratoire des Venins et Biomolécules Thérapeutiques, Institut Pasteur de Tunis, Tunisia. maram.morjen@yahoo.fr
authors.forename: Maram
authors.initials: M
authors.lastname: Morjen
authors.forename: Olfa
authors.initials: O
authors.lastname: Kallech-Ziri
authors.forename: Amine
authors.initials: A
authors.lastname: Bazaa
authors.forename: Houcemeddine
authors.initials: H
authors.lastname: Othman
authors.forename: Kamel
authors.initials: K
authors.lastname: Mabrouk
authors.forename: Raoudha
authors.initials: R
authors.lastname: Zouari-Kessentini
authors.forename: Libia
authors.initials: L
authors.lastname: Sanz
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Calvete
authors.forename: Najet
authors.initials: N
authors.lastname: Srairi-Abid
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Ayeb
authors.forename: José
authors.initials: J
authors.lastname: Luis
authors.forename: Naziha
authors.initials: N
authors.lastname: Marrakchi
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D007928:Lethal Dose 50; D018715:Microscopy, Video; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D011487:Protein Conformation; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D053719:Tandem Mass Spectrometry; D059008:Time-Lapse Imaging; D014416:Tunisia; D014757:Viper Venoms / Q000737:chemistry*; D017819:Viperidae / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D039302:Integrin alphaVbeta3; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D014757:Viper Venoms