H-Prune through GSK-3β interaction sustains canonical WNT/β-catenin signaling enhancing cancer progression in NSCLC

Abstract

// Marianeve Carotenuto 1,2 , Pasqualino De Antonellis 1,2 , Lucia Liguori 1,2 , Giovanna Benvenuto 3 , Daniela Magliulo 1,2 , Alessandro Alonzi 1,2 , Cecilia Turino 4 , Carmela Attanasio 1,2 , Valentina Damiani 1,2 , Anna Maria Bello 1,2 , Fabiana Vitiello 5 , Rosa Pasquinelli 6 , Luigi Terracciano 7 , Antonella Federico 8 , Alfredo Fusco 8 , Jamie Freeman 9 , Trevor C. Dale 9 , Charles Decraene 10,11 , Gennaro Chiappetta 6 , Francovito Piantedosi 5 , Cecilia Calabrese 4 and Massimo Zollo 1,2,12 1 Centro di Ingegneria Genetica e Biotecnologie Avanzate (CEINGE), Naples, Italy 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università ‘Federico II’ di Naples, Italy 3 Stazione Zoologica Anthon Dohrn, Villa Comunale, Naples, Italy 4 Dipartimento di Scienze Cardiotoraciche e Respiratorie, Clinica Seconda Università degli Studi di Napoli, Naples, Italy 5 Dipartimento di Pneumologia e Tisiologia, Day Hospital Pneumologia e Pneumoncologico, AORN Vincenzo Monaldi, Naples, Italy 6 Functional Genomic Unit, National Cancer Institute, Fondazione G. Pascale, Naples, Italy 7 Institute of Pathology, Molecular Pathology Division, University of Basel, Switzerland 8 Dipartimento di Biologia e Patologia Cellulare e Molecolare, Istituto Di Endocrinologia e Oncologia Sperimentale del CNR, Naples, Italy 9 School of Biosciences, Cardiff University, Museum Avenue, Cardiff, Wales, UK 10 Translational Research Dept, Institut Curie, Centre de recherche, Paris, France 11 CNRS, UMR144, Paris, France 12 Azienda Ospedaliera Federico II, DAI Medicina Trasfusionale, Naples, Italy Correspondence: Massimo Zollo1, email: // Keywords : h-Prune, lung cancer, diagnostic marker, WNT/β-catenin signalling, Gsk-3β, Wnt3a Received : June 18, 2014 Accepted : July 4, 2014 Published : July 5, 2014 Abstract H-Prune  hydrolyzes short-chain polyphosphates (PPase activity) together with an hitherto cAMP-phosphodiesterase (PDE), the latest influencing different human cancers by its overexpression. H-Prune promotes cell migration in cooperation with glycogen synthase kinase-3 (Gsk-3β). Gsk-3β is a negative regulator of canonical WNT/β-catenin signaling. Here, we investigate the role of Gsk-3β/h-Prune complex in the regulation of WNT/β-catenin signaling, demonstrating the h-Prune capability to activate WNT signaling also in a paracrine manner, through Wnt3a secretion. In vivo study demonstrates that h-Prune silencing inhibits lung metastasis formation, increasing mouse survival. We assessed h-Prune levels in peripheral blood of lung cancer patients using ELISA assay, showing that h-Prune is an early diagnostic marker for lung cancer. Our study dissects out the mechanism of action of h-Prune in tumorigenic cells and also sheds light on the identification of a new therapeutic target in non-small-cell lung cancer.