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.

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. - 35:4(2021), pp. 1-11. [10.1016/j.celrep.2021.109024]

Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth

Soldano A.;Quattrone A.
2021-01-01

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.
2021
35
4
1
11
109024
10.1016/j.celrep.2021.109024
https://pubmed.ncbi.nlm.nih.gov/33910005/
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.
File in questo prodotto:
File Dimensione Formato  
Cell Reports_Sighel et al. 2021.pdf

non disponibili

Descrizione: pdf editoriale
Tipologia: Versione Editoriale (PDF)
Licenza: Creative commons
Dimensione 6.13 MB
Formato Adobe PDF
6.13 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/133291
Citazioni
  • ???jsp.display-item.citation.pmc??? 29
  • Scopus 34
  • ???jsp.display-item.citation.isi??? 35
social impact