Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide

Abstract The integrated stress response (ISR) is a central cellular adaptive program that is activated by diverse stressors including ER stress, hypoxia and nutrient deprivation to orchestrate responses via activating transcription factor 4 (ATF4). We hypothesized that ATF4 is essential for the adap...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Nadja I. Lorenz, Alina C. M. Sittig, Hans Urban, Anna-Luisa Luger, Anna L. Engel, Christian Münch, Joachim P. Steinbach, Michael W. Ronellenfitsch
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0736b208a57543ffb304b79c8033e560
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:0736b208a57543ffb304b79c8033e560
record_format	dspace
spelling	oai:doaj.org-article:0736b208a57543ffb304b79c8033e5602021-12-02T15:22:56ZActivating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide10.1038/s41598-021-93663-12045-2322https://doaj.org/article/0736b208a57543ffb304b79c8033e5602021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93663-1https://doaj.org/toc/2045-2322Abstract The integrated stress response (ISR) is a central cellular adaptive program that is activated by diverse stressors including ER stress, hypoxia and nutrient deprivation to orchestrate responses via activating transcription factor 4 (ATF4). We hypothesized that ATF4 is essential for the adaptation of human glioblastoma (GB) cells to the conditions of the tumor microenvironment and is contributing to therapy resistance against chemotherapy. ATF4 induction in GB cells was modulated pharmacologically and genetically and investigated in the context of temozolomide treatment as well as glucose and oxygen deprivation. The relevance of the ISR was analyzed by cell death and metabolic measurements under conditions to approximate aspects of the GB microenvironment. ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.Nadja I. LorenzAlina C. M. SittigHans UrbanAnna-Luisa LugerAnna L. EngelChristian MünchJoachim P. SteinbachMichael W. RonellenfitschNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nadja I. Lorenz Alina C. M. Sittig Hans Urban Anna-Luisa Luger Anna L. Engel Christian Münch Joachim P. Steinbach Michael W. Ronellenfitsch Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide
description	Abstract The integrated stress response (ISR) is a central cellular adaptive program that is activated by diverse stressors including ER stress, hypoxia and nutrient deprivation to orchestrate responses via activating transcription factor 4 (ATF4). We hypothesized that ATF4 is essential for the adaptation of human glioblastoma (GB) cells to the conditions of the tumor microenvironment and is contributing to therapy resistance against chemotherapy. ATF4 induction in GB cells was modulated pharmacologically and genetically and investigated in the context of temozolomide treatment as well as glucose and oxygen deprivation. The relevance of the ISR was analyzed by cell death and metabolic measurements under conditions to approximate aspects of the GB microenvironment. ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.
format	article
author	Nadja I. Lorenz Alina C. M. Sittig Hans Urban Anna-Luisa Luger Anna L. Engel Christian Münch Joachim P. Steinbach Michael W. Ronellenfitsch
author_facet	Nadja I. Lorenz Alina C. M. Sittig Hans Urban Anna-Luisa Luger Anna L. Engel Christian Münch Joachim P. Steinbach Michael W. Ronellenfitsch
author_sort	Nadja I. Lorenz
title	Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide
title_short	Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide
title_full	Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide
title_fullStr	Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide
title_full_unstemmed	Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide
title_sort	activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0736b208a57543ffb304b79c8033e560
work_keys_str_mv	AT nadjailorenz activatingtranscriptionfactor4mediatesadaptationofhumanglioblastomacellstohypoxiaandtemozolomide AT alinacmsittig activatingtranscriptionfactor4mediatesadaptationofhumanglioblastomacellstohypoxiaandtemozolomide AT hansurban activatingtranscriptionfactor4mediatesadaptationofhumanglioblastomacellstohypoxiaandtemozolomide AT annaluisaluger activatingtranscriptionfactor4mediatesadaptationofhumanglioblastomacellstohypoxiaandtemozolomide AT annalengel activatingtranscriptionfactor4mediatesadaptationofhumanglioblastomacellstohypoxiaandtemozolomide AT christianmunch activatingtranscriptionfactor4mediatesadaptationofhumanglioblastomacellstohypoxiaandtemozolomide AT joachimpsteinbach activatingtranscriptionfactor4mediatesadaptationofhumanglioblastomacellstohypoxiaandtemozolomide AT michaelwronellenfitsch activatingtranscriptionfactor4mediatesadaptationofhumanglioblastomacellstohypoxiaandtemozolomide
_version_	1718387366496829440

Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide

Ejemplares similares