Mitoribosomal synthetic lethality overcomes multidrug resistance in MYC-driven neuroblastoma

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F23%3A00079676" target="_blank" >RIV/00159816:_____/23:00079676 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14310/23:00133019

Result on the web

<a href="https://www.nature.com/articles/s41419-023-06278-x" target="_blank" >https://www.nature.com/articles/s41419-023-06278-x</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41419-023-06278-x" target="_blank" >10.1038/s41419-023-06278-x</a>

Result language

angličtina

Original language name

Mitoribosomal synthetic lethality overcomes multidrug resistance in MYC-driven neuroblastoma

Original language description

Mitochondria are central for cancer responses to therapy-induced stress signals. Refractory tumors often show attenuated sensitivity to apoptotic signaling, yet clinically relevant molecular actors to target mitochondria-mediated resistance remain elusive. Here, we show that MYC-driven neuroblastoma cells rely on intact mitochondrial ribosome (mitoribosome) processivity and undergo cell death following pharmacological inhibition of mitochondrial translation, regardless of their multidrug/mitochondrial resistance and stem-like phenotypes. Mechanistically, inhibiting mitoribosomes induced the mitochondrial stress-activated integrated stress response (ISR), leading to downregulation of c-MYC/N-MYC proteins prior to neuroblastoma cell death, which could be both rescued by the ISR inhibitor ISRIB. The ISR blocks global protein synthesis and shifted the c-MYC/N-MYC turnover toward proteasomal degradation. Comparing models of various neuroectodermal tumors and normal fibroblasts revealed overexpression of MYC proteins phosphorylated at the degradation-promoting site T58 as a factor that predetermines vulnerability of MYC-driven neuroblastoma to mitoribosome inhibition. Reducing N-MYC levels in a neuroblastoma model with tunable MYCN expression mitigated cell death induction upon inhibition of mitochondrial translation and functionally validated the propensity of neuroblastoma cells for MYC-dependent cell death in response to the mitochondrial ISR. Notably, neuroblastoma cells failed to develop significant resistance to the mitoribosomal inhibitor doxycycline over a long-term repeated (pulsed) selection. Collectively, we identify mitochondrial translation machinery as a novel synthetic lethality target for multidrug-resistant MYC-driven tumors.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10601 - Cell biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cell Death &amp; Disease

ISSN

2041-4889

e-ISSN

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Volume of the periodical

14

Issue of the periodical within the volume

11

Country of publishing house

US - UNITED STATES

Number of pages

17

Pages from-to

747

UT code for WoS article

001104524100001

EID of the result in the Scopus database

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