Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity

Autores
Barontini, Marta Beatriz; López Sambrooks, Cecilia; Quijano, Amanda; Mark Saltzman, W.; Contessa, Joseph
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Purpose: Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)–targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization. Experimental Design: We investigated the effects of a small-molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy-induced cell toxicity, DNA damage, and cell-cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by in vivo molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation-independent CD8-EGFR chimera. Results: NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G 1 cell-cycle arrest. Combined treatment of glioma xenografts with fractionated radiotherapy and NGI-1 significantly reduced tumor growth compared with controls. Expression of the CD8-EGFR eliminated the effects of NGI-1 on G 1 arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect. Conclusions: This study suggests that oligosaccharyltransferase inhibition with NGI-1 is a novel approach to radio-sensitize malignant gliomas with enhanced RTK signaling.
Fil: Barontini, Marta Beatriz. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: López Sambrooks, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. University of Yale; Estados Unidos
Fil: Quijano, Amanda. University of Yale; Estados Unidos
Fil: Mark Saltzman, W.. University of Yale; Estados Unidos
Fil: Contessa, Joseph. University of Yale. School of Medicine; Estados Unidos
Materia
RTK
Radiosensitization
Oligosaccharyltransferase
N-glycosylation
Glioma
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/95857

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network_name_str CONICET Digital (CONICET)
spelling Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivityBarontini, Marta BeatrizLópez Sambrooks, CeciliaQuijano, AmandaMark Saltzman, W.Contessa, JosephRTKRadiosensitizationOligosaccharyltransferaseN-glycosylationGliomahttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Purpose: Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)–targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization. Experimental Design: We investigated the effects of a small-molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy-induced cell toxicity, DNA damage, and cell-cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by in vivo molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation-independent CD8-EGFR chimera. Results: NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G 1 cell-cycle arrest. Combined treatment of glioma xenografts with fractionated radiotherapy and NGI-1 significantly reduced tumor growth compared with controls. Expression of the CD8-EGFR eliminated the effects of NGI-1 on G 1 arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect. Conclusions: This study suggests that oligosaccharyltransferase inhibition with NGI-1 is a novel approach to radio-sensitize malignant gliomas with enhanced RTK signaling.Fil: Barontini, Marta Beatriz. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: López Sambrooks, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. University of Yale; Estados UnidosFil: Quijano, Amanda. University of Yale; Estados UnidosFil: Mark Saltzman, W.. University of Yale; Estados UnidosFil: Contessa, Joseph. University of Yale. School of Medicine; Estados UnidosAmerican Association for Cancer Research2019-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/95857Barontini, Marta Beatriz; López Sambrooks, Cecilia; Quijano, Amanda; Mark Saltzman, W.; Contessa, Joseph; Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity; American Association for Cancer Research; Clinical Cancer Research; 25; 2; 1-2019; 784-7951078-0432CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/content/early/2018/11/12/1078-0432.CCR-18-0792.longinfo:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-18-0792info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:10:36Zoai:ri.conicet.gov.ar:11336/95857instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:10:36.43CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity
title Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity
spellingShingle Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity
Barontini, Marta Beatriz
RTK
Radiosensitization
Oligosaccharyltransferase
N-glycosylation
Glioma
title_short Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity
title_full Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity
title_fullStr Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity
title_full_unstemmed Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity
title_sort Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity
dc.creator.none.fl_str_mv Barontini, Marta Beatriz
López Sambrooks, Cecilia
Quijano, Amanda
Mark Saltzman, W.
Contessa, Joseph
author Barontini, Marta Beatriz
author_facet Barontini, Marta Beatriz
López Sambrooks, Cecilia
Quijano, Amanda
Mark Saltzman, W.
Contessa, Joseph
author_role author
author2 López Sambrooks, Cecilia
Quijano, Amanda
Mark Saltzman, W.
Contessa, Joseph
author2_role author
author
author
author
dc.subject.none.fl_str_mv RTK
Radiosensitization
Oligosaccharyltransferase
N-glycosylation
Glioma
topic RTK
Radiosensitization
Oligosaccharyltransferase
N-glycosylation
Glioma
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Purpose: Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)–targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization. Experimental Design: We investigated the effects of a small-molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy-induced cell toxicity, DNA damage, and cell-cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by in vivo molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation-independent CD8-EGFR chimera. Results: NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G 1 cell-cycle arrest. Combined treatment of glioma xenografts with fractionated radiotherapy and NGI-1 significantly reduced tumor growth compared with controls. Expression of the CD8-EGFR eliminated the effects of NGI-1 on G 1 arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect. Conclusions: This study suggests that oligosaccharyltransferase inhibition with NGI-1 is a novel approach to radio-sensitize malignant gliomas with enhanced RTK signaling.
Fil: Barontini, Marta Beatriz. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: López Sambrooks, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; Argentina. University of Yale; Estados Unidos
Fil: Quijano, Amanda. University of Yale; Estados Unidos
Fil: Mark Saltzman, W.. University of Yale; Estados Unidos
Fil: Contessa, Joseph. University of Yale. School of Medicine; Estados Unidos
description Purpose: Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)–targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization. Experimental Design: We investigated the effects of a small-molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy-induced cell toxicity, DNA damage, and cell-cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by in vivo molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation-independent CD8-EGFR chimera. Results: NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G 1 cell-cycle arrest. Combined treatment of glioma xenografts with fractionated radiotherapy and NGI-1 significantly reduced tumor growth compared with controls. Expression of the CD8-EGFR eliminated the effects of NGI-1 on G 1 arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect. Conclusions: This study suggests that oligosaccharyltransferase inhibition with NGI-1 is a novel approach to radio-sensitize malignant gliomas with enhanced RTK signaling.
publishDate 2019
dc.date.none.fl_str_mv 2019-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/95857
Barontini, Marta Beatriz; López Sambrooks, Cecilia; Quijano, Amanda; Mark Saltzman, W.; Contessa, Joseph; Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity; American Association for Cancer Research; Clinical Cancer Research; 25; 2; 1-2019; 784-795
1078-0432
CONICET Digital
CONICET
url http://hdl.handle.net/11336/95857
identifier_str_mv Barontini, Marta Beatriz; López Sambrooks, Cecilia; Quijano, Amanda; Mark Saltzman, W.; Contessa, Joseph; Oligosaccharyltransferase inhibition reduces receptor tyrosine kinase activation and enhances glioma radiosensitivity; American Association for Cancer Research; Clinical Cancer Research; 25; 2; 1-2019; 784-795
1078-0432
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/content/early/2018/11/12/1078-0432.CCR-18-0792.long
info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-18-0792
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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