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

19 Citations (Scopus)

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

Fingerprint

Lymphoma
Ribosomal Proteins
Mitochondrial Proteins
Neoplasms
Maintenance
Anti-Bacterial Agents
Biological Phenomena
Therapeutics
Reverse Genetics
myc Genes
B-Cell Lymphoma
Cell Survival
Transcription Factors
Messenger RNA
Genes

Keywords

  • Lymphoma
  • Mitochondria
  • Mitochondrial translation
  • Myc
  • Tigecycline

ASJC Scopus subject areas

  • Oncology

Cite this

The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas. / D'Andrea, Aleco; Gritti, Ilaria; Nicoli, Paola; Giorgio, Marco; Doni, Mirko; Conti, Annalisa; Bianchi, Valerio; Casoli, Lucia; Sabò, Arianna; Mironov, Alexandre; Beznoussenko, Galina V.; Amati, Bruno.

In: Oncotarget, Vol. 7, No. 45, 2016, p. 72415-72430.

Research output: Contribution to journalArticle

D'Andrea, A, Gritti, I, Nicoli, P, Giorgio, M, Doni, M, Conti, A, Bianchi, V, Casoli, L, Sabò, A, Mironov, A, Beznoussenko, GV & Amati, B 2016, 'The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas', Oncotarget, vol. 7, no. 45, pp. 72415-72430. https://doi.org/10.18632/oncotarget.11719
D'Andrea, Aleco ; Gritti, Ilaria ; Nicoli, Paola ; Giorgio, Marco ; Doni, Mirko ; Conti, Annalisa ; Bianchi, Valerio ; Casoli, Lucia ; Sabò, Arianna ; Mironov, Alexandre ; Beznoussenko, Galina V. ; Amati, Bruno. / The mitochondrial translation machinery as a therapeutic target in Myc-driven lymphomas. In: Oncotarget. 2016 ; Vol. 7, No. 45. pp. 72415-72430.
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