TY - JOUR
T1 - Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth
AU - Sighel, Denise
AU - Notarangelo, Michela
AU - Aibara, Shintaro
AU - Re, Angela
AU - Ricci, Gianluca
AU - Guida, Marianna
AU - Soldano, Alessia
AU - Adami, Valentina
AU - Ambrosini, Chiara
AU - Broso, Francesca
AU - Rosatti, Emanuele Filiberto
AU - Longhi, Sara
AU - Buccarelli, Mariachiara
AU - D'Alessandris, Quintino G.
AU - Giannetti, Stefano
AU - Pacioni, Simone
AU - Ricci-Vitiani, Lucia
AU - Rorbach, Joanna
AU - Pallini, Roberto
AU - Roulland, Sandrine
AU - Amunts, Alexey
AU - Mancini, Ines
AU - Modelska, Angelika
AU - Quattrone, Alessandro
N1 - Funding Information:
This work was supported by Fondazione Giovanni Celeghin Onlus and by a donation from Ivana and Enrico Zobele (to A.Q.). This work was also supported by the Swedish Foundation for Strategic Research ( FFL15:0325 ), the Ragnar Söderberg Foundation ( M44/16 ), the Swedish Research Council ( NT_2015-04107 ), Cancerfonden ( CAN 2017/1041 ), the European Research Council ( ERC-2018-StG-805230 ), the Knut and Alice Wallenberg Foundation ( 2018.0080 ) (to A.A.), the FEBS Long-Term Fellowship Program (to S.A.), an EMBO short-term fellowship (to A.M.), a postdoctoral fellowship (CRISPR Screen Action) from the Canceropôle Provence-Alpes-Côte d’Azur , the French National Cancer Institute (INCa), the Provence-Alpes-Côte d’Azur Region (to J.R.) , and the AIRC Foundation ( IG 2019 Id.23154 to R.P.). The graphical abstract was created with BioRender. COMI and VIPI cells were a kind gift from Antonio Daga (Azienda Ospedaliera Universitaria San Martino di Genova, Italy) and 030616 from Rossella Galli (H.S. Raffaele, Milan, Italy). The human GSC lines GB6, GB7, GB8, G144, and G166 and the human fetal neural stem cell lines CB660 and U3 were kind gifts from Luciano Conti (Department CIBIO, University of Trento). We thank the HTS, CASF, CT, and the Imaging Core Facilities of CIBIO for assistance with experimentation. We thank Camilla Maffezzini at the Karolinska Institute for help with BN-PAGE and in-gel activity assay. The cryo-EM data were collected at the Swedish National Facility funded by the Knut and Alice Wallenberg Foundation , Family Erling Persson Foundation, and Kempe Foundation. We thank M. Carroni, J.M. de la Rosa Trevin, and S. Fleischmann for smooth data collection and processing.
Funding Information:
This work was supported by Fondazione Giovanni Celeghin Onlus and by a donation from Ivana and Enrico Zobele (to A.Q.). This work was also supported by the Swedish Foundation for Strategic Research (FFL15:0325), the Ragnar S?derberg Foundation (M44/16), the Swedish Research Council (NT_2015-04107), Cancerfonden (CAN 2017/1041), the European Research Council (ERC-2018-StG-805230), the Knut and Alice Wallenberg Foundation (2018.0080) (to A.A.), the FEBS Long-Term Fellowship Program (to S.A.), an EMBO short-term fellowship (to A.M.), a postdoctoral fellowship (CRISPR Screen Action) from the Cancerop?le Provence-Alpes-C?te d'Azur, the French National Cancer Institute (INCa), the Provence-Alpes-C?te d'Azur Region (to J.R.), and the AIRC Foundation (IG 2019 Id.23154 to R.P.). The graphical abstract was created with BioRender. COMI and VIPI cells were a kind gift from Antonio Daga (Azienda Ospedaliera Universitaria San Martino di Genova, Italy) and 030616 from Rossella Galli (H.S. Raffaele, Milan, Italy). The human GSC lines GB6, GB7, GB8, G144, and G166 and the human fetal neural stem cell lines CB660 and U3 were kind gifts from Luciano Conti (Department CIBIO, University of Trento). We thank the HTS, CASF, CT, and the Imaging Core Facilities of CIBIO for assistance with experimentation. We thank Camilla Maffezzini at the Karolinska Institute for help with BN-PAGE and in-gel activity assay. The cryo-EM data were collected at the Swedish National Facility funded by the Knut and Alice Wallenberg Foundation, Family Erling Persson Foundation, and Kempe Foundation. We thank M. Carroni, J.M. de la Rosa Trevin, and S. Fleischmann for smooth data collection and processing. Conceptualization, A.M. and A.Q.; methodology, D.S. and A.M.; formal analysis, A.R.; investigation, D.S. M.N. S.A. G.R. V.A. M.G. A.S. C.A. F.B. E.F.R. M.B. Q.G.D. S.G. S.P. R.P. A.A. and A.M.; writing ? original draft, A.M.; writing ? review & editing, A.M. D.S. and A.Q.; funding acquisition, A.M. A.Q. and A.A.; resources, A.Q. L.R.-V. R.P. J.R. A.A. S.R. and I.M.; supervision, A.M. and A.Q. D.S. I.M. A.M. and A.Q. have applied for protection of intellectual property related to the results in the manuscript and to Q/D analogs in cancer therapy (Italian patent number 102020000012601).
Publisher Copyright:
© 2021 The Authors
PY - 2021/4/27
Y1 - 2021/4/27
N2 - 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.
AB - 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.
KW - cryo-EM
KW - dalfopristin
KW - drug repurposing
KW - glioblastoma
KW - glioblastoma stem cells
KW - high-content screening
KW - mitochondrial translation
KW - mitoribosome
KW - OXPHOS
KW - quinupristin
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U2 - 10.1016/j.celrep.2021.109024
DO - 10.1016/j.celrep.2021.109024
M3 - Article
C2 - 33910005
AN - SCOPUS:85105041390
VL - 35
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
M1 - 109024
ER -