Sighel 2021 Cell Rep

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Publications in the MiPMap
Sighel D, Notarangelo M, Aibara S, Re A, Ricci G, Guida M, Soldano A, Adami V, Ambrosini C, Broso F, Rosatti EF, Longhi S, Buccarelli M, D'Alessandris QG, Giannetti S, Pacioni S, Ricci-Vitiani L, Rorbach J, Pallini R, Roulland S, Amunts A, Mancini I, Modelska A, Quattrone A (2021) Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth. Cell Rep 35:109024.

» PMID: 33910005 Open Access

Sighel Denise, Notarangelo Michela, Aibara Shintaro, Re Angela, Ricci Gianluca, Guida Marianna, Soldano Alessia, Adami Valentina, Ambrosini Chiara, Broso Francesca, Rosatti Emanuele Filiberto, Longhi Sara, Buccarelli Mariachiara, D'Alessandris Quintino G, Giannetti Stefano, Pacioni Simone, Ricci-Vitiani Lucia, Rorbach Joanna, Pallini Roberto, Roulland Sandrine, Amunts Alexey, Mancini Ines, Modelska Angelika, Quattrone Alessandro (2021) Cell Rep

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 Bioblast editor: Reiswig R O2k-Network Lab: IT Bolzano Pichler I


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cancer 

Organism: Human  Tissue;cell: Nervous system, Stem cells  Preparation: Permeabilized cells, Intact cells  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: ROUTINE, OXPHOS  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k 

2021-08