Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes

Abstract Glioblastoma (GBM) is the most aggressive brain primary malignancy. Toll-like receptor 4 (TLR4) has a dual role in cell fate, promoting cell survival or death depending on the context. Here, we analyzed TLR4 expression in different grades of astrocytoma, and observed increased expression in...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Isabele F. Moretti, Antonio M. Lerario, Marina Trombetta-Lima, Paula R. Sola, Roseli da Silva Soares, Sueli M. Oba-Shinjo, Suely K. N. Marie
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dbd539efc27248eda907583955f9ce84
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:dbd539efc27248eda907583955f9ce84
record_format	dspace
spelling	oai:doaj.org-article:dbd539efc27248eda907583955f9ce842021-12-02T14:12:43ZLate p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes10.1038/s41598-020-79356-12045-2322https://doaj.org/article/dbd539efc27248eda907583955f9ce842021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79356-1https://doaj.org/toc/2045-2322Abstract Glioblastoma (GBM) is the most aggressive brain primary malignancy. Toll-like receptor 4 (TLR4) has a dual role in cell fate, promoting cell survival or death depending on the context. Here, we analyzed TLR4 expression in different grades of astrocytoma, and observed increased expression in tumors, mainly in GBM, compared to non-neoplastic brain tissue. TLR4 role was investigated in U87MG, a GBM mesenchymal subtype cell line, upon LPS stimulation. p65 nuclear translocation was observed in late phase, suggesting TLR4-non-canonical pathway activation. In fact, components of ripoptosome and inflammasome cascades were upregulated and they were significantly correlated in GBMs of the TCGA-RNASeq dataset. Moreover, an increased apoptotic rate was observed when the GBM-derived U87MG cells were co-treated with LPS and Temozolomide (TMZ) in comparison to TMZ alone. Increased TLR4 immunostaining was detected in nuclei of U87MG cells 12 h after LPS treatment, concomitant to activation of DNA repair genes. Time-dependent increased RAD51, FEN1 and UNG expression levels were confirmed after LPS stimulation, which may contribute to tumor cell fitness. Moreover, the combined treatment with the RAD51 inhibitor, Amuvatinib in combination with, TMZ after LPS stimulation reduced tumor cell viability more than with each treatment alone. In conclusion, our results suggest that stimulation of TLR4 combined with pharmacological inhibition of the DNA repair pathway may be an alternative treatment for GBM patients.Isabele F. MorettiAntonio M. LerarioMarina Trombetta-LimaPaula R. SolaRoseli da Silva SoaresSueli M. Oba-ShinjoSuely K. N. MarieNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Isabele F. Moretti Antonio M. Lerario Marina Trombetta-Lima Paula R. Sola Roseli da Silva Soares Sueli M. Oba-Shinjo Suely K. N. Marie Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes
description	Abstract Glioblastoma (GBM) is the most aggressive brain primary malignancy. Toll-like receptor 4 (TLR4) has a dual role in cell fate, promoting cell survival or death depending on the context. Here, we analyzed TLR4 expression in different grades of astrocytoma, and observed increased expression in tumors, mainly in GBM, compared to non-neoplastic brain tissue. TLR4 role was investigated in U87MG, a GBM mesenchymal subtype cell line, upon LPS stimulation. p65 nuclear translocation was observed in late phase, suggesting TLR4-non-canonical pathway activation. In fact, components of ripoptosome and inflammasome cascades were upregulated and they were significantly correlated in GBMs of the TCGA-RNASeq dataset. Moreover, an increased apoptotic rate was observed when the GBM-derived U87MG cells were co-treated with LPS and Temozolomide (TMZ) in comparison to TMZ alone. Increased TLR4 immunostaining was detected in nuclei of U87MG cells 12 h after LPS treatment, concomitant to activation of DNA repair genes. Time-dependent increased RAD51, FEN1 and UNG expression levels were confirmed after LPS stimulation, which may contribute to tumor cell fitness. Moreover, the combined treatment with the RAD51 inhibitor, Amuvatinib in combination with, TMZ after LPS stimulation reduced tumor cell viability more than with each treatment alone. In conclusion, our results suggest that stimulation of TLR4 combined with pharmacological inhibition of the DNA repair pathway may be an alternative treatment for GBM patients.
format	article
author	Isabele F. Moretti Antonio M. Lerario Marina Trombetta-Lima Paula R. Sola Roseli da Silva Soares Sueli M. Oba-Shinjo Suely K. N. Marie
author_facet	Isabele F. Moretti Antonio M. Lerario Marina Trombetta-Lima Paula R. Sola Roseli da Silva Soares Sueli M. Oba-Shinjo Suely K. N. Marie
author_sort	Isabele F. Moretti
title	Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes
title_short	Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes
title_full	Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes
title_fullStr	Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes
title_full_unstemmed	Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes
title_sort	late p65 nuclear translocation in glioblastoma cells indicates non-canonical tlr4 signaling and activation of dna repair genes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/dbd539efc27248eda907583955f9ce84
work_keys_str_mv	AT isabelefmoretti latep65nucleartranslocationinglioblastomacellsindicatesnoncanonicaltlr4signalingandactivationofdnarepairgenes AT antoniomlerario latep65nucleartranslocationinglioblastomacellsindicatesnoncanonicaltlr4signalingandactivationofdnarepairgenes AT marinatrombettalima latep65nucleartranslocationinglioblastomacellsindicatesnoncanonicaltlr4signalingandactivationofdnarepairgenes AT paularsola latep65nucleartranslocationinglioblastomacellsindicatesnoncanonicaltlr4signalingandactivationofdnarepairgenes AT roselidasilvasoares latep65nucleartranslocationinglioblastomacellsindicatesnoncanonicaltlr4signalingandactivationofdnarepairgenes AT suelimobashinjo latep65nucleartranslocationinglioblastomacellsindicatesnoncanonicaltlr4signalingandactivationofdnarepairgenes AT suelyknmarie latep65nucleartranslocationinglioblastomacellsindicatesnoncanonicaltlr4signalingandactivationofdnarepairgenes
_version_	1718391816125939712

Late p65 nuclear translocation in glioblastoma cells indicates non-canonical TLR4 signaling and activation of DNA repair genes

Ejemplares similares