title: The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas.
abstract: The oncogenic transcription factor Myc is required for the progression and maintenance of diverse tumors. This has led to the concept that Myc itself, Myc-activated gene products, or associated biological processes might constitute prime targets for cancer therapy. Here, we present an in vivo reverse-genetic screen targeting a set of 241 Myc-activated mRNAs in mouse B-cell lymphomas, unraveling a critical role for the mitochondrial ribosomal protein (MRP) Ptcd3 in tumor maintenance. Other MRP-coding genes were also up regulated in Myc-induced lymphoma, pointing to a coordinate activation of the mitochondrial translation machinery. Inhibition of mitochondrial translation with the antibiotic Tigecycline was synthetic-lethal with Myc activation, impaired respiratory activity and tumor cell survival in vitro, and significantly extended lifespan in lymphoma-bearing mice. We have thus identified a novel Myc-induced metabolic dependency that can be targeted by common antibiotics, opening new therapeutic perspectives in Myc-overexpressing tumors.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Aleco
authors.initials: A
authors.lastname: D'Andrea
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Present address: IRCCS San Raffaele, Functional Genomics of Cancer Unit, Division of Experimental Oncology, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Gritti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Doni
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Conti
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.|Present address: Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan, Utrecht, The Netherlands.
authors.forename: Valerio
authors.initials: V
authors.lastname: Bianchi
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Casoli
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Sabò
authors.affiliation: The Institute of Molecular Oncology of the Italian Foundation for Cancer Research, Milan, Italy.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mironov
authors.affiliation: The Institute of Molecular Oncology of the Italian Foundation for Cancer Research, Milan, Italy.
authors.forename: Galina V
authors.initials: GV
authors.lastname: Beznoussenko
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
mesh_terms: D000818:Animals; D029681:Arabidopsis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008911:Minocycline / Q000031:analogs & derivatives / Q000494:pharmacology; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000078304:Tigecycline; D023041:Xenograft Model Antitumor Assays; D024101:Mitochondrial Proteins
chemical_list: D029681:Arabidopsis Proteins; D008911:Minocycline; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D000078304:Tigecycline; C489427:MYC protein, human; C489428:Myc protein, mouse; C000597732:PTCD3 protein, human; D024101:Mitochondrial Proteins
keywords: Myc; Tigecycline; lymphoma; mitochondria; mitochondrial translation