Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET

Kód výsledku v IS VaVaI

RIV/61989592:15110/23:73619176 - isvavai.cz

Výsledek na webu

https://www.nature.com/articles/s41418-023-01167-4

DOI - Digital Object Identifier

10.1038/s41418-023-01167-4

Jazyk výsledku

angličtina

Název v původním jazyce

Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET

Popis výsledku v původním jazyce

Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcoholdependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that thedisulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregaseto suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxiceffects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, andmechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diversehuman cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed byfeatures of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein andits functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomicsprofiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolongedexposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneouspharmacological inhibition of RiBi and/or autophagy that further enhanced CuET’s tumor cytotoxicity, using both cell culture andzebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET’s anti-cancer activity, informabout the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in lightof cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET inoncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, ratherthan old, approved drugs with their, often complex, metabolic profiles.

Název v anglickém jazyce

Actionable cancer vulnerability due to translational arrest, p53 aggregation and ribosome biogenesis stress evoked by the disulfiram metabolite CuET

Popis výsledku anglicky

Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcoholdependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that thedisulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregaseto suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxiceffects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, andmechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diversehuman cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed byfeatures of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein andits functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomicsprofiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolongedexposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneouspharmacological inhibition of RiBi and/or autophagy that further enhanced CuET’s tumor cytotoxicity, using both cell culture andzebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET’s anti-cancer activity, informabout the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in lightof cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET inoncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, ratherthan old, approved drugs with their, often complex, metabolic profiles.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

GA20-28685S: Identifikace a strukturní charakterizace nových inhibitorů proteinu NPL4 a vhled do jejich mechanismu účinku

Návaznosti

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

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

CELL DEATH AND DIFFERENTIATION

ISSN

1350-9047

e-ISSN

1476-5403

Svazek periodika

30

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

13

Strana od-do

1666-1678

Kód UT WoS článku

000981375200003

EID výsledku v databázi Scopus

2-s2.0-85158032323