Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth

Denise Sighel, Michela Notarangelo, Shintaro Aibara, Angela Re, Gianluca Ricci, Marianna Guida, Alessia Soldano, Valentina Adami, Chiara Ambrosini, Francesca Broso, Emanuele Filiberto Rosatti, Sara Longhi, Mariachiara Buccarelli, Quintino G. D'Alessandris, Stefano Giannetti, Simone Pacioni, Lucia Ricci-Vitiani, Joanna Rorbach, Roberto Pallini, Sandrine RoullandAlexey Amunts, Ines Mancini, Angelika Modelska, Alessandro Quattrone

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma stem cells (GSCs) resist current glioblastoma (GBM) therapies. GSCs rely highly on oxidative phosphorylation (OXPHOS), whose function requires mitochondrial translation. Here we explore the therapeutic potential of targeting mitochondrial translation and report the results of high-content screening with putative blockers of mitochondrial ribosomes. We identify the bacterial antibiotic quinupristin/dalfopristin (Q/D) as an effective suppressor of GSC growth. Q/D also decreases the clonogenicity of GSCs in vitro, consequently dysregulating the cell cycle and inducing apoptosis. Cryoelectron microscopy (cryo-EM) reveals that Q/D binds to the large mitoribosomal subunit, inhibiting mitochondrial protein synthesis and functionally dysregulating OXPHOS complexes. These data suggest that targeting mitochondrial translation could be explored to therapeutically suppress GSC growth in GBM and that Q/D could potentially be repurposed for cancer treatment.

Original languageEnglish
Article number109024
JournalCell Reports
Volume35
Issue number4
DOIs
Publication statusPublished - Apr 27 2021

Keywords

  • cryo-EM
  • dalfopristin
  • drug repurposing
  • glioblastoma
  • glioblastoma stem cells
  • high-content screening
  • mitochondrial translation
  • mitoribosome
  • OXPHOS
  • quinupristin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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