Priority Research Papers:
The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas
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Aleco D’Andrea1, Ilaria Gritti1,4, Paola Nicoli1, Marco Giorgio1, Mirko Doni1, Annalisa Conti2, Valerio Bianchi2,5, Lucia Casoli2, Arianna Sabò2, Alexandre Mironov3, Galina V. Beznoussenko3 and Bruno Amati1,2
1 Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
2 Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy
3 The Institute of Molecular Oncology of the Italian Foundation for Cancer Research, Milan, Italy
4 Present address: IRCCS San Raffaele, Functional Genomics of Cancer Unit, Division of Experimental Oncology, Milan, Italy
5 Present address: Hubrecht Institute-KNAW & University Medical Center Utrecht, Uppsalalaan, Utrecht, The Netherlands
Bruno Amati, email:
Keywords: lymphoma, mitochondria, mitochondrial translation, Myc, Tigecycline
Received: June 20, 2016 Accepted: August 25, 2016 Published: August 31, 2016
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.
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