Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth

Denise Sighel; Michela Notarangelo; Shintaro Aibara; Angela Re; Gianluca Ricci; Giuseppe Ricci; Marianna Guida; Alessia Soldano; Valentina Adami; Chiara Ambrosini; Francesca Broso; Emanuele Filiberto Rosatti; Sara Longhi; Mariachiara Buccarelli; Quintino Giorgio 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

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

Risultato della ricerca: Contributo in rivista › Articolo in rivista

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.

Lingua originale	English
pagine (da-a)	N/A-N/A
Rivista	Cell Reports
Volume	35
DOI	https://doi.org/10.1016/j.celrep.2021.109024
Stato di pubblicazione	Pubblicato - 2021

Keywords

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

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10.1016/j.celrep.2021.109024

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Sighel, D., Notarangelo, M., Aibara, S., Re, A., Ricci, G., 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., ... Quattrone, A. (2021). Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth. Cell Reports, 35, N/A-N/A. https://doi.org/10.1016/j.celrep.2021.109024

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title = "Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth",

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, OXPHOS, cryo-EM, dalfopristin, drug repurposing, glioblastoma, glioblastoma stem cells, high-content screening, mitochondrial translation, mitoribosome, quinupristin",

author = "Denise Sighel and Michela Notarangelo and Shintaro Aibara and Angela Re and Gianluca Ricci and Giuseppe Ricci and Marianna Guida and Alessia Soldano and Valentina Adami and Chiara Ambrosini and Francesca Broso and Rosatti, {Emanuele Filiberto} and Sara Longhi and Mariachiara Buccarelli and D'Alessandris, {Quintino Giorgio} and Stefano Giannetti and Simone Pacioni and Lucia Ricci-Vitiani and Joanna Rorbach and Roberto Pallini and Sandrine Roulland and Alexey Amunts and Ines Mancini and Angelika Modelska and Alessandro Quattrone",

year = "2021",

doi = "10.1016/j.celrep.2021.109024",

language = "English",

volume = "35",

pages = "N/A--N/A",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier B.V.",

}

Sighel, D, Notarangelo, M, Aibara, S, Re, A, Ricci, G, 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 Reports, vol. 35, pagg. N/A-N/A. https://doi.org/10.1016/j.celrep.2021.109024

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 - Ricci, Giuseppe

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 Giorgio

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

PY - 2021

Y1 - 2021

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 - OXPHOS

KW - cryo-EM

KW - dalfopristin

KW - drug repurposing

KW - glioblastoma

KW - glioblastoma stem cells

KW - high-content screening

KW - mitochondrial translation

KW - mitoribosome

KW - quinupristin

KW - OXPHOS

KW - cryo-EM

KW - dalfopristin

KW - drug repurposing

KW - glioblastoma

KW - glioblastoma stem cells

KW - high-content screening

KW - mitochondrial translation

KW - mitoribosome

KW - quinupristin

UR - http://hdl.handle.net/10807/218996

U2 - 10.1016/j.celrep.2021.109024

DO - 10.1016/j.celrep.2021.109024

M3 - Article

SN - 2211-1247

VL - 35

SP - N/A-N/A

JO - Cell Reports

JF - Cell Reports

ER -

Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth

Abstract

Keywords

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