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 Roulland; Alexey Amunts; Ines Mancini; Angelika Modelska; Alessandro Quattrone

doi:10.1016/j.celrep.2021.109024

Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth

Cell Rep. 2021 Apr 27;35(4):109024. doi: 10.1016/j.celrep.2021.109024.

Authors

Denise Sighel¹, Michela Notarangelo², Shintaro Aibara³, Angela Re⁴, Gianluca Ricci², Marianna Guida⁵, Alessia Soldano², Valentina Adami², Chiara Ambrosini², Francesca Broso², Emanuele Filiberto Rosatti², Sara Longhi², Mariachiara Buccarelli⁶, Quintino G D'Alessandris⁷, Stefano Giannetti⁸, Simone Pacioni⁷, Lucia Ricci-Vitiani⁶, Joanna Rorbach⁹, Roberto Pallini⁷, Sandrine Roulland¹⁰, Alexey Amunts³, Ines Mancini¹¹, Angelika Modelska¹², Alessandro Quattrone¹³

Affiliations

¹ Department CIBIO, University of Trento, Trento 38123, Italy. Electronic address: denise.sighel@unitn.it.
² Department CIBIO, University of Trento, Trento 38123, Italy.
³ Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm 171 65, Sweden.
⁴ Department CIBIO, University of Trento, Trento 38123, Italy; Centre for Sustainable Future Technologies, Fondazione Istituto Italiano di Tecnologia, Torino 10144, Italy.
⁵ EURAC Research, Bolzano 39100, Italy.
⁶ Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
⁷ Institute of Neurosurgery, Università Cattolica del Sacro Cuore, IRCCS Fondazione Policlinico A. Gemelli, Rome 00168, Italy.
⁸ Institute of Biology, Università Cattolica del Sacro Cuore, Rome 00168, Italy.
⁹ Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 171 65, Sweden.
¹⁰ Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
¹¹ Department of Physics, University of Trento, Trento 38123, Italy.
¹² Department CIBIO, University of Trento, Trento 38123, Italy; Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France. Electronic address: a.modelska@gmail.com.
¹³ Department CIBIO, University of Trento, Trento 38123, Italy. Electronic address: alessandro.quattrone@unitn.it.

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.

Keywords: OXPHOS; cryo-EM; dalfopristin; drug repurposing; glioblastoma; glioblastoma stem cells; high-content screening; mitochondrial translation; mitoribosome; quinupristin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation
Glioblastoma / genetics*
Humans
Mitochondria / metabolism*
Neoplastic Stem Cells / metabolism*