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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/95857
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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 |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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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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13.13397 |