title: IGFBP-3 inhibits Wnt signaling in metastatic melanoma cells.
abstract: In previous works, we have shown that insulin-like growth factor-binding protein-3 (IGFBP-3), a tissue and circulating protein able to bind to IGFs, decreases drastically in the blood serum of patients with diffuse metastatic melanoma. In agreement with the clinical data, recombinant IGFBP-3 was found to inhibit the motility and invasiveness of cultured metastatic melanoma cells and to prevent growth of grafted melanomas in mice. The present work was aimed at identifying the signal transduction pathways underlying the anti-tumoral effects of IGFBP-3. We show that the anti-tumoral effect of IGFBP-3 is due to inhibition of the Wnt pathway and depends upon the presence of CD44, a receptor protein known to modulate Wnt signaling. Once it has entered the cell, IGFBP-3 binds the Wnt signalosome interacting specifically with its component GSK-3β. As a consequence, the β-catenin destruction complex dissociates from the LRP6 Wnt receptor and GSK-3β is activated through dephosphorylation, becoming free to target cytoplasmic β-catenin which is degraded by the proteasomal pathway. Altogether, the results suggest that IGFBP-3 is a novel and effective inhibitor of Wnt signaling. As IGFBP-3 is a physiological protein which has no detectable toxic effects either on cultured cells or live mice, it might qualify as an interesting new therapeutic agent in melanoma, and potentially many other cancers with a hyperactive Wnt signaling. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.
authors.affiliation: Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Antimo
authors.initials: A
authors.lastname: Naspi
authors.affiliation: Laboratory of Microscopic and Ultrastructural Anatomy, School of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Zingariello
authors.affiliation: Department of Medicine and Aging Sciences, Section of Human Morphology, University G. D'Annunzio, Chieti, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Sancillo
authors.affiliation: Plastic and Reconstructive Surgery Unit, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Panasiti
authors.affiliation: Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Dorina
authors.initials: D
authors.lastname: Polinari
authors.affiliation: Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Martella
authors.affiliation: Department of Medicine and Aging Sciences, Section of Human Morphology, University G. D'Annunzio, Chieti, Italy.
authors.forename: Rana
authors.initials: R
authors.lastname: Rosa Alba
authors.affiliation: Department of Cellular Biotechnologies and Haematology, Istituto Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Londei
mesh_terms: D000818:Animals; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D060066:Protein Interaction Maps; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018960:Hyaluronan Receptors; D018972:Insulin-Like Growth Factor Binding Protein 3; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex
keywords: IGFBP-3; Wnt; melanoma