The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas

Aleco D'Andrea, Ilaria Gritti, Paola Nicoli, Marco Giorgio, Mirko Doni, Annalisa Conti, Valerio Bianchi, Lucia Casoli, Arianna Sabò, Alexandre Mironov, Galina V. Beznoussenko, Bruno Amati

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)72415-72430
Number of pages16
JournalOncotarget
Volume7
Issue number45
DOIs
Publication statusPublished - 2016

Keywords

  • Lymphoma
  • Mitochondria
  • Mitochondrial translation
  • Myc
  • Tigecycline

ASJC Scopus subject areas

  • Oncology

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