Archivio Istituzionale della RicercaGlioblastoma 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.
Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth / Sighel, D.; Notarangelo, M.; Aibara, S.; Re, A.; Ricci, G.; Guida, M.; Soldano, A.; Adami, V.; Ambrosini, C.; Broso, F.; Rosatti, E. F.; Longhi, S.; Buccarelli, M.; D'Alessandris, Q. G.; Giannetti, S.; Pacioni, S.; Ricci-Vitiani, L.; Rorbach, J.; Pallini, R.; Roulland, S.; Amunts, A.; Mancini, I.; Modelska, A.; Quattrone, A.. - In: CELL REPORTS. - ISSN 2211-1247. - STAMPA. - 35:4(2021), pp. 10902401-10902427. [10.1016/j.celrep.2021.109024]
Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth
Re A.;
2021
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.
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https://hdl.handle.net/11583/2970520