title: Expression and activity of eIF6 trigger malignant pleural mesothelioma growth in vivo.
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.
authors.affiliation: Molecular Histology and Cell Growth Unit, Istituto Nazionale Genetica Molecolare, "Romeo ed Enrica Invernizzi", Milano, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Miluzio
authors.affiliation: Molecular Histology and Cell Growth Unit, Istituto Nazionale Genetica Molecolare, "Romeo ed Enrica Invernizzi", Milano, Italy.|Dipartimento di Scienze e Innovazione Tecnologica, University of Eastern Piedmont, Alessandria, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Oliveto
authors.affiliation: Molecular Histology and Cell Growth Unit, Istituto Nazionale Genetica Molecolare, "Romeo ed Enrica Invernizzi", Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pesce
authors.affiliation: Biomedicine Institute, The University of Salford, The Crescent, Salford, UK.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mutti
authors.affiliation: Hospital Dall'Angelo, Pathology Unit, Venice, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Murer
authors.affiliation: Medical Research Council Toxicology Unit, Leicester, UK.
authors.forename: Stefano
authors.initials: S
authors.lastname: Grosso
authors.affiliation: Molecular Histology and Cell Growth Unit, Istituto Nazionale Genetica Molecolare, "Romeo ed Enrica Invernizzi", Milano, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ricciardi
authors.affiliation: Molecular Histology and Cell Growth Unit, Istituto Nazionale Genetica Molecolare, "Romeo ed Enrica Invernizzi", Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Brina
authors.affiliation: Molecular Histology and Cell Growth Unit, Istituto Nazionale Genetica Molecolare, "Romeo ed Enrica Invernizzi", Milano, Italy.|Department of Biosciences, University of Milan, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability; D034622:RNA Interference; D000067492:RNAi Therapeutics; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C109284:EIF6 protein, human; D039642:Eukaryotic Initiation Factors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C579054:PRKCB protein, human; D064546:Protein Kinase C beta; C504878:enzastaurin
keywords: Enzastaurin; PKCbeta; anti-association activity; eIF6 phosphorylation; malignant pleural mesothelioma