Expression and activity of eIF6 trigger Malignant Pleural Mesothelioma growthin vivo

// Annarita Miluzio 1, * , Stefania Oliveto 1, 2, * , Elisa Pesce 1 , Luciano Mutti 3 , Bruno Murer 4 , Stefano Grosso 5 , Sara Ricciardi 1 , Daniela Brina 1 , Stefano Biffo 1, 6 1 Molecular Histology and Cell Growth Unit, Istituto Nazionale Genetica Molecolare, “Romeo ed Enrica Invernizzi”, Milano, Italy 2 Dipartimento di Scienze e Innovazione Tecnologica, University of Eastern Piedmont, Alessandria, Italy 3 Biomedicine Institute, The University of Salford, The Crescent, Salford, UK 4 Hospital Dall’Angelo, Pathology Unit, Venice, Italy 5 Medical Research Council Toxicology Unit, Leicester, UK 6 Department of Biosciences, University of Milan, Milan, Italy * These authors have contributed equally to this work Correspondence to: Stefano Biffo, e-mail: Stefano.biffo@unimi.it Keywords: Malignant Pleural Mesothelioma, eIF6 phosphorylation, anti-association activity, PKCbeta, Enzastaurin Received: March 18, 2015 Accepted: September 24, 2015 Published: October 06, 2015 ABSTRACT eIF6 is an antiassociation factor that regulates the availability of active 80S. Its activation is driven by the RACK1/PKCβ axis, in a mTORc1 independent manner. We previously described that eIF6 haploinsufficiency causes a striking survival in the Eμ-Myc mouse lymphoma model, with lifespans extended up to 18 months. Here we screen for eIF6 expression in human cancers. We show that Malignant Pleural Mesothelioma tumors (MPM) and a MPM cell line (REN cells) contain high levels of hyperphosphorylated eIF6. Enzastaurin is a PKC beta inhibitor used in clinical trials. We prove that Enzastaurin treatment decreases eIF6 phosphorylation rate, but not eIF6 protein stability. The growth of REN, in vivo , and metastasis are reduced by either Enzastaurin treatment or eIF6 shRNA. Molecular analysis reveals that eIF6 manipulation affects the metabolic status of malignant mesothelioma cells. Less glycolysis and less ATP content are evident in REN cells depleted for eIF6 or treated with Enzastaurin (Anti-Warburg effect). We propose that eIF6 is necessary for malignant mesothelioma growth, in vivo , and can be targeted by kinase inhibitors.