Publication: Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth

Publié dans: Cell Reports, 2021, 35 (4), pp.109024. ⟨10.1016/j.celrep.2021.109024⟩

Auteurs: 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 D’alessandris, Stefano Giannetti, Simone Pacioni, Lucia Ricci-Vitiani, Joanna Rorbach, Roberto Pallini, Sandrine Roulland, Alexey Amunts, Ines Mancini, Angelika Modelska, Alessandro Quattrone

Résumé

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.

Lien vers HAL – amu-04091882

Lien vers le DOI – 10.1016/j.celrep.2021.109024