title: Midkine lacking its last 40 amino acids acts on endothelial and neuroblastoma tumor cells and inhibits tumor development.
abstract: Midkine (MDK) is a member of a new family of neurotrophic factors considered as rate-limiting growth and angiogenic factors implicated in the onset, invasion, and metastatic process of neuronal tumors, including neuroblastoma. We showed that all neuroblastoma cell lines highly expressed MDK, indicating that it is a critical player in tumor development, which may henceforth represent an attractive therapeutic target. We showed that the knockdown of MDK expression by siRNA led to a marked and significant decrease in neuroblastoma (IGR-N91 and SH-SY5Y) cell proliferation in vitro. Using a new strategy, we then evaluated the antitumor effect of a truncated MDK protein, lacking the C-terminal 81-121 portion of the molecule (MDKΔ81-121), which may act as a dominant-negative effector for its mitogenic, angiogenic, and tumorigenic activities by heterodimerizing with the wild-type protein. In vitro studies showed that MDKΔ81-121 selectively inhibited MDK-dependent tumor cells and was able to strongly reduce endothelial cell proliferation and migration and to induce ER stress-mediated apoptosis. We then investigated the effects of MDKΔ81-121 in vivo using electrotransfer of a plasmid encoding a secretable form of MDKΔ81-121 into tibialis cranialis muscles of nude mice. We showed that MDKΔ81-121 dramatically inhibited (up to 91%) tumor development and growth. This inhibition was correlated with the detection of the MDKΔ81-121 molecule in plasma and the suppression of intratumor neovascularization. Our findings demonstrate that MDK inhibition is a tractable therapeutic target for this lethal pediatric malignancy.
authors.affiliation: INSERM U745, Laboratoire de Génétique Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France.
authors.forename: Noushin
authors.initials: N
authors.lastname: Dianat
authors.affiliation: INSERM U745, Laboratoire de Génétique Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Paris, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Le Viet
authors.affiliation: INSERM U935, Human Embryonic Stem Cell Core Facility, Villejuif, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Gobbo
authors.affiliation: Départements de Biologie et Pathologie Médicale, Institute Gustave-Roussy, Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auger
authors.affiliation: Laboratoire d'Oncogénétique, Institut Curie, Hôpital René Huguenin, St-Cloud, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: INSERM U935, Human Embryonic Stem Cell Core Facility, Villejuif, France. Université Paris-Sud 11, Campus Orsay, Orsay, France.
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.affiliation: INSERM U935, Human Embryonic Stem Cell Core Facility, Villejuif, France. Départements de Biologie et Pathologie Médicale, Institute Gustave-Roussy, Villejuif, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Sciences Pharmaceutiques et Biologiques, Paris, France. franck.griscelli@igr.fr.
authors.forename: Frank
authors.initials: F
authors.lastname: Griscelli
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D000078792:Midkine; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009447:Neuroblastoma / Q000098:blood supply / Q000628:therapy*; D010957:Plasmids / Q000235:genetics
chemical_list: D016207:Cytokines; D000078792:Midkine