Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth

D. Sighel; M. Notarangelo; S. Aibara; A. Re; G. Ricci; M. Guida; A. Soldano; V. Adami; C. Ambrosini; F. Broso; E. F. Rosatti; S. Longhi; M. Buccarelli; Quintino Giorgio D'Alessandris; Stefano Giannetti; Simone Pacioni; L. Ricci-Vitiani; J. Rorbach; R. Pallini; S. Roulland; A. Amunts; I. Mancini; A. Modelska; A. Quattrone

doi:10.1016/j.celrep.2021.109024

Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth

D. Sighel^*
, M. Notarangelo
, S. Aibara
, A. Re
, G. Ricci
, M. Guida
, A. Soldano
, V. Adami
, C. Ambrosini
, F. Broso
, E. F. Rosatti
, S. Longhi
, M. Buccarelli
, Quintino Giorgio D'Alessandris
, Stefano Giannetti
, Simone Pacioni
, L. Ricci-Vitiani
, J. Rorbach
, R. Pallini
, S. Roulland

A. Amunts, I. Mancini, A. Modelska^*, A. Quattrone^*

^*Autore corrispondente per questo lavoro

University of Trento
Stockholm University
Italian Institute of Technology
EURAC Research
Istituto Superiore di Sanita
Max Planck Institute for Biology of Ageing
Centre dImmunologie de Marseille-Luminy

Risultato della ricerca: Contributo in rivista › Articolo

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	Inglese
pagine (da-a)	N/A-N/A
Rivista	Cell Reports
Volume	35
Numero di pubblicazione	4
DOI	https://doi.org/10.1016/j.celrep.2021.109024
Stato di pubblicazione	Pubblicato - 2021

OSS delle Nazioni Unite

Questo processo contribuisce al raggiungimento dei seguenti obiettivi di sviluppo sostenibile

SDG 3 Salute e benessere

All Science Journal Classification (ASJC) codes

Biochimica, Genetica, Biologia Molecolare Generali

Keywords

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

Accesso al documento

10.1016/j.celrep.2021.109024

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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., ... Quattrone, A. (2021). Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth. Cell Reports, 35(4), 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.",

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author = "D. Sighel and M. Notarangelo and S. Aibara and A. Re and G. Ricci and M. Guida and A. Soldano and V. Adami and C. Ambrosini and F. Broso and Rosatti, \{E. F.\} and S. Longhi and M. Buccarelli and D'Alessandris, \{Quintino Giorgio\} and Stefano Giannetti and Simone Pacioni and L. Ricci-Vitiani and J. Rorbach and R. Pallini and S. Roulland and A. Amunts and I. Mancini and A. Modelska and A. Quattrone",

year = "2021",

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

language = "English",

volume = "35",

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journal = "Cell Reports",

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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 Reports, vol. 35, n. 4, 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, D.

AU - Notarangelo, M.

AU - Aibara, S.

AU - Re, A.

AU - Ricci, G.

AU - Guida, M.

AU - Soldano, A.

AU - Adami, V.

AU - Ambrosini, C.

AU - Broso, F.

AU - Rosatti, E. F.

AU - Longhi, S.

AU - Buccarelli, M.

AU - D'Alessandris, Quintino Giorgio

AU - Giannetti, Stefano

AU - Pacioni, Simone

AU - Ricci-Vitiani, L.

AU - Rorbach, J.

AU - Pallini, R.

AU - Roulland, S.

AU - Amunts, A.

AU - Mancini, I.

AU - Modelska, A.

AU - Quattrone, A.

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.

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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 - https://publicatt.unicatt.it/handle/10807/218996

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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

IS - 4

ER -

Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth

Abstract

OSS delle Nazioni Unite

All Science Journal Classification (ASJC) codes

Keywords

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